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3
Evolution of Centralized
Nervous Systems:
Two Schools of Evolutionary Thought
R. GLENN NORTHCUTT
Understanding the evolution of centralized nervous systems requires an
understanding of metazoan phylogenetic interrelationships, their fossil
record, the variation in their cephalic neural characters, and the devel-
opment of these characters. Each of these topics involves comparative
approaches, and both cladistic and phenetic methodologies have been
applied. Our understanding of metazoan phylogeny has increased greatly
with the cladistic analysis of molecular data, and relaxed molecular clocks
generally date the origin of bilaterians at 600–700 Mya (during the Edia-
caran). Although the taxonomic affinities of the Ediacaran biota remain
uncertain, a conservative interpretation suggests that a number of these
taxa form clades that are closely related, if not stem clades of bilaterian
crown clades. Analysis of brain–body complexity among extant bilateri-
ans indicates that diffuse nerve nets and, possibly, ganglionated cephalic
neural systems existed in Ediacaran organisms. An outgroup analysis of
cephalic neural characters among extant metazoans also indicates that
the last common bilaterian ancestor possessed a diffuse nerve plexus
and that brains evolved independently at least four times. In contrast,
the hypothesis of a tripartite brain, based primarily on phenetic analysis
of developmental genetic data, indicates that the brain arose in the last
common bilaterian ancestor. Hopefully, this debate will be resolved by
Laboratory of Comparative Neurobiology, Scripps Institution of Oceanography and Depart-
ment of Neurosciences, University of California at San Diego, La Jolla, CA 92093. E-mail:
rgnorthcutt@ucsd.edu.
37
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38 / R. Glenn Northcutt
cladistic analysis of the genomes of additional taxa and an increased
understanding of character identity genetic networks.
The fact that some of these building stones are universal does not, of
course, mean that the organs to which they contribute are as old as these
molecules or their precursors.
von Salvini-Plawen and Mayr (1977)
A
ny consideration of the evolution of centralized nervous systems is
inextricably linked to an understanding of the phylogeny of living
metazoans, their fossil history, the vast range of complexity in their
nervous systems, and the development of these nervous systems. For this
reason, any attempt to reconstruct the phylogeny of metazoan CNSs must
be based on all lines of evidence available. The molecular phylogenetic
studies of the last 20 years are particularly important in understanding
metazoan interrelationships as well as the time frame in which these
animals arose and radiated, and we now have increased insights into the
genetics underlying the development of CNSs.
First, I will review the fossil history of the earliest putative metazoans,
and then, I will discuss different comparative approaches to analyzing
both molecular and morphological data: the molecular clock hypothesis,
which has yielded a range of possible dates for the origin and divergence
of metazoans; developmental genetics and its contribution to our under-
standing of the patterning of metazoan bodies, particularly patterning
of the CNS; and conclusions based on the first outgroup analysis of
metazoan central neural characters. Finally, I will review two hypotheses
concerning the morphological complexity of the last common bilaterian
ancestor.
FOSSIL RECORD
The fossil record is notoriously incomplete. Fossils essentially exist
as snapshots in time, and these snapshots are of varying quality. Some
are grainy, providing only a glimpse of organisms and their ecology;
others are fine-grained photographs of individual taxa and their ecology
(Lagerstätten). Regardless, each snapshot provides unique and criti-
cal insights into the minimal age of a radiation. Each snapshot helps
calibrate molecular clocks, establish ecological settings of evolutionary
events, and reveal unsuspected morphological characters that challenge
current conclusions regarding character transformation (Donoghue and
Purnell, 2009).
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Evolution of Centralized Nervous Systems / 39
Ediacaran Biota
The earliest reported fossils of possible metazoan embryos and adults
are in the Ediacaran Doushantuo Formation (~570 Mya) in southern China
(Xiao et al., 1998; Chen et al., 2000, 2009). Small globular fossils, ~200 μm
in diameter, show remarkable cellular details and have been interpreted
as cnidarian gastrulae and planulae as well as bilaterian gastrulae compa-
rable with living molluscans and echinoderms (Chen et al., 2000). How-
ever, the interpretation of these fossils as bilaterian metazoans has been
questioned, and they have been reinterpreted as encysted holozoan pro-
tists (Huldtgren et al., 2011). Similar problems plague the earliest reported
adult bilaterian, Vernanimalcula, which is also from the Doushantuo For-
mation of southern China (Chen et al., 2004a,b). Fossils of Vernanimalcula
(~200 μm in diameter) have been described as broadly oval and triploblas-
tic with a mouth, a differentiated gut surrounded by paired coeloms, and
an anus. The rostral end of these “small spring animals” is also reported
to have three pairs of external pits that have been interpreted as sensory
organs (Chen et al., 2004a). This interpretation has been questioned, how-
ever, and these fossils have been claimed to be taphonomic artifacts in
which phosphates were deposited within a spherical object, such as the
cysts of algal acritarchs (Bengtson and Budd, 2004).
The earliest fossils of macroscopic organisms interpreted as metazo-
ans, including bilaterians, are in the Ediacaran strata above the Doushan-
tuo Formation (Fedonkin et al., 2007). They average 10 cm but reach an
extreme of 1 m in length, and they include forms that are frond-, disk-, and
worm-like (Fig. 3.1A); their interpretation has had a tumultuous history.
Many of these fossils were discovered in the late 1940s and were inter-
preted as representatives of living metazoan phyla. Forms like Eoporpita
(Fig. 3.1A, 1) were interpreted as cnidarian pelagic medusa (Glaessner,
1984), and frond-like forms, such as Charniodiscus (Fig. 3.1A, 2), were
interpreted as possible cnidarian sea pins (Glaessner, 1962). Still other
forms of these fossils were interpreted as stem bilaterians. For example,
Dickinsonia (Fig. 3.1A, 3) was interpreted as a flatworm (Glaessner and
Wade, 1966), Arkarua (Fig. 3.1A, 4) was interpreted as an echinoderm
(Gehling, 1987), Spriggina (Fig. 3.1A, 5) was interpreted as an annelid
capable of active swimming (Birket-Smith, 1981), and Praecambridium
(Fig. 3.1A, 6) and a soft-bodied “trilobite” not formally described (Fig.
3.1A, 7) were interpreted as stem arthropods (Glaessner and Wade, 1971;
Gehling, 1991). After this burst of descriptions, Ediacaran anatomy was
reevaluated; claims were made that all Ediacarans were organized on a
quilt-like pattern and represented an independent experiment of nonmeta-
zoan animals, termed the Vendobionta, that failed with the evolution of
macrophagous bilaterian metazoans (Seilacher, 1989; Buss and Seilacher,
1994; McMenamin, 1998). The concept of the Ediacaran biota as Vendo-
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40
FIGURE 3.1 Reconstruction of the Ediacaran (A) and Burgess Shale (B) biotas. The Ediacaran biota is reconstructed to convey
maximal morphological complexity. (A) 1, Eoporpita; 2, Charniodiscus; 3, Dickinsonia; 4, Arkarua; 5, Spriggina; 6, Praecambridium; 7,
soft-bodied “trilobite”; 8, Kimberella. (B) 1, Burgessochaeta; 2, Lingulella; 3, Ottoia; 4, Marrella; 5, Olenoides; 6, Naraoia; 7, Canadaspis;
8, Sidneyia, 9, Opabinia; 10, Anomalocaris; 11, Gogia; 12, Eldonia; 13, Pikaia; 14, Aysheaia; 15, Hallucigenia; 16, Odontogriphus; 17, Dino-
mischus.
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Evolution of Centralized Nervous Systems / 41
bionta was generally abandoned, because paleontologists came to realize
that the Ediacaran biota represents a wide range of morphological forms
(Fedonkin et al., 2007; Erwin et al., 2011).
To date, the Ediacaran biota includes some 160 taxa (Fedonkin et al.,
2007) found in 40 separate locations representing all parts of the globe
except Antarctica. These biotas are dispersed among three stratigraphic
zones in named assemblages based on a cladistic analysis of their spatial
and temporal distribution (Waggoner, 2003): an Avalon assemblage (579
to ~560 Mya), a White Sea assemblage (~560 to ~550 Mya), and a Nama
assemblage (~550–541 Mya).
The Avalon assemblage is dominated by simple, frond-like taxa, such
as Charnia, grouped into a clade termed the Rangeomorpha (Erwin et al.,
2011). Macroscopic bilaterians are absent from the Avalon assemblage as
well as trace fossils, such as surface tracks or shallow horizontal burrows,
that would indicate the presence of small bilaterians that had developed
muscles and coeloms to hydraulically locomote. One could infer from the
Avalon assemblage that small bilaterians had not yet evolved, but this
assemblage is the only Ediacaran assemblage from deep water; therefore,
it is possible that small locomotory bilaterians existed at this time but
were restricted to shallow ecological zones (Bottjer and Clapham, 2006).
The White Sea assemblage represents the peak diversity of Ediacaran
biota, including all of the taxa in Fig. 3.1A, which are grouped into nine
clades (Erwin et al., 2011). The clade Kimberellomorpha is of particular
interest, because it includes Kimberella (Fig. 3.1A, 8), a small, oval-shaped
animal that seems to have glided on a muscular foot and have an anterior
end that houses a retractable arrow-shaped organ that was used to scratch
the upper surface of the microbial mats on which it moved (Fedonkin and
Waggoner, 1997; Jensen et al., 2006). Trace fossils in the White Sea assem-
blage are diverse and suggest the presence of small bilaterians (Erwin et
al., 2011).
The Nama assemblage has less diversity than either the Avalon or
White Sea assemblages, and it is dominated by frond-like taxa, called
arboreomorphs, and simple cylindrical, sessile taxa, called erniettomorphs
(Waggoner, 2003; Erwin et al., 2011). Bilaterian body fossils are absent,
but small calcified shells of Cloudina and Namacalathus and the earliest
evidence of predation in the form of holes bored into these calcified shells
do occur (Bengtson and Zhao, 1992).
Our understanding of body organization and phylogeny of Edia-
carans is incomplete, but a conservative interpretation of the paleonto-
logical data indicates that most animals existed primarily on microbial
mats; it was likely a 2D world, with sessile frond-like forms and vagile,
small organisms that trophically were suspension feeders and grazers.
There is little to no evidence that pelagic medusae existed (Fig. 3.1A, 1),
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42 / R. Glenn Northcutt
but there is considerable evidence that sponges and sessile cnidarians
were scattered across the microbial mats as were a number of bag-, frond-,
and spindle-shaped taxa, forming clades that may be unrelated to any
living metazoans. One or more of the three radiations of the small vagile
organisms may be close relatives, or even stem members, of three clades
of extant metazoans.
Cambrian Explosion
The close of the Ediacaran was marked by a massive reduction in the
Ediacaran biota, with only a small number of Ediacaran taxa continuing
into the Early Cambrian (Conway Morris, 1993). The small, calcified shells
first seen in the late Ediacaran continue to diversify, however, in the early
Cambrian to include a wide variety of plates, spines, and small shelly fauna,
which seem to be the skeletal elements of bilaterians that ranged from a few
millimeters to several centimeters in length (Matthews and Missarzhevsky,
1975). Clearly, bilaterians became armored in the Ediacaran–Cambrian
transition. This finding suggests that the development of hard mouth
parts may have been a key innovation to allow for additional expansion
of macrophagous predators, giving rise to the first arms race (Bengtson
and Zhao, 1992). The small shelly taxa diversified over the next 14 Myr,
which culminated in the Cambrian explosion of bilaterian diversity; this
explosion seems to have occurred over a relatively short 10 Myr (Conway
Morris, 2000b). Despite the rapidity of the Cambrian explosion, we have
two fine-grained snapshots of the event captured in the exceptionally
well-preserved, soft-bodied Lagerstätten of the Chengjiang biota of the
early Cambrian (~525 Mya) from the Yunan Province in South China
and the Burgess Shale biota of the Middle Cambrian (~505 Mya) from
British Columbia. Each of these biotas has been extensively described
(Whittington, 1985; Briggs et al., 1994; Chen et al., 1997; Conway Morris,
1998; Xian-Guang et al., 2004) and analyzed for community composition
and structure (Conway Morris, 1986; Zhao et al., 2010).
Despite the Chengjiang and Burgess Shale biotas existing in distinctly
different environments—the Chengjiang community is thought to have
existed in a relatively shallow marine environment, possibly a partially
enclosed embayment subject to periodic, storm-generated turbidity (Chen
et al., 1997; Zhao et al., 2010), whereas the Burgess Shale biota is thought
to have existed as a deep-water community on muddy sediments banked
against the front of a stromatolite reef (Fig. 3.1B), where it was thus
unstable and subject to periodic slumps, carrying parts of the community
into deeper, anaerobic waters (Whittington, 1985; Briggs et al., 1994)—
both communities share numerous similarities. Both were dominated by
arthropods, brachiopods, and priapulid worms (Conway Morris, 1986;
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Evolution of Centralized Nervous Systems / 43
Zhao et al., 2010). Approximately 20% of each fauna consisted of sessile or
burrowing infaunal species, and each fauna was dominated by epifaunal
species, only 4% of which were pelagic. Feeding strategies included sus-
pension feeding and hunting/scavenging, forming complex food chains
comparable with those food chains in many modern benthic marine eco-
systems (Castro and Huber, 1992). Members of stem and/or crown groups
at the bilaterian phylum level are in these Cambrian communities and
occupy niches similar to those niches in modern benthic marine ecosys-
tems, suggesting that competition among taxa was as high then as it is
now. For example, in the Burgess Shale biota, infaunal species included
polychaete annelids such as Burgessochaeta (Fig. 3.1B, 1), brachiopods such
as Lingulella (Fig. 3.1B, 2), and priapulid worms such as Ottoia (Fig. 3.1B,
3), which seems to have been an aggressive predator (Briggs et al., 1994).
Epifaunal taxa included suspension- and detritus-feeding arthropods such
as Marrella (Fig. 3.1B, 4), the trilobites Olenoides (Fig. 3.1B, 5) and Naraoia
(Fig. 3.1B, 6), and a possible crustacean, Canadaspis (Fig. 3.1B, 7), as well
as predatory arthropods such as Sidneyia (Fig. 3.1B, 8), Opabinia (Fig. 3.1B,
9), and Anomalocaris (Fig. 3.1B, 10), which grew to over 1 m in length and
were clearly apex predators. Deuterostomes are also represented in the
Cambrian biota of the Burgess Shale: the eocrinoid echinoderm Gogia (Fig.
3.1B, 11) and a possible pelagic holothurian, Eldonia (Fig. 3.1B, 12), as well
as a possible cephalochordate, Pikaia (Fig. 3.1B, 13).
Unlike the Burgess Shale biota, the Chengjiang biota contains a rich
variety of chordates. Two sessile, putative urochordates, Cheungkongella
and Shankouclava, have been described (Shu et al., 2001; Chen et al., 2003)
as well as another Pikaia-like chordate, Yunnanozoon, which was initially
described as a possible cephalochordate with a notochord, segmented
trunk muscles, and an expanded pharynx with an endostyle (Chen et al.,
1995). This taxon was subsequently reinterpreted as an early vertebrate
(Dzik, 1995), and it was then reinterpreted again as the earliest known
enteropneust hemichordate (Shu et al., 1996b). Subsequently, a third
Pikaia-like taxon, Cathaymyrus, was described in the Chengjiang deposits
and interpreted as a cephalochordate (Shu et al., 1996a).
Early craniates (hagfishes and vertebrates) may also occur in the
Chenjiang biota. Haikouella has been interpreted as a craniate-like chor-
date with a well-developed brain, lateral eyes, a pharynx with gills,
and a ventral heart (Chen et al., 1999; Mallatt et al., 2003). A subsequent
interpretation of the Haikouella material suggests that the head consisted
of separate dorsal and ventral movable units connected by external gills
(Shu et al., 2003) and that Yunnanozoon and Haikouella are stem group
deuterostomes that are allied to vetulicolians, another problematic group
in the Chengjiang biota (Shu et al., 2003, 2010). Thus, the yunnanozoans
(Yunnanozoon, Cathaymyrus, and Haikouella) may be stem cephalochor-
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dates, or they may be closely allied to vetulicolians and may possibly be
stem deuterostomes.
The situation is somewhat clearer regarding the first vertebrates from
the Chengjiang Lagerstätte. Two genera, Haikouichthys and Myllokun-
mingia, have been described as agnathan vertebrates, with Haikouichthys
said to be closely allied to living lampreys and Myllokunmingia said to be
closely allied to living hagfishes (Shu et al., 1999). However, it has been
claimed that this interpretation is based on tenuous characters and that
both taxa may form a clade (myllokunmingids) that is basal to living
craniates (Janvier, 2003, 2008). Subsequently, another described genus,
Zhongjianichthys, seems to be a myllokunmingid (Shu, 2003). In any case,
these taxa seem to have had paired nasal capsules, large lateral eyes, and,
possibly, paired otic capsules, all of which suggest that they may have
possessed brains comparable with living agnathan vertebrates (Shu, 2003).
Similar taxonomic problems plague a number of the Burgess Shale
taxa. Aysheaia (Fig. 3.1B, 14) and Hallucigenia (Fig. 3.1B, 15) have been
considered to be primitive onychophoran worms (Briggs et al., 1994) but
are more probably an extinct clade (the lobopods, which were possibly
a stem group of arthropods) (Budd and Telford, 2009). This finding is
also true of Opabinia (Fig. 3.1B, 9) and Anomalocaris (Fig. 3.1B, 10), which
may be members of a clade of stem arthropods, although their exact
relationship to other arthropods is still unclear (Budd and Telford, 2009).
Odontogriphus (Fig. 3.1B, 16), a pelagic, flattened, 12-cm-long animal with
tooth-like elements surrounding the mouth, remains an enigma but may
be a basal lophotrochozoan related to annelids, brachiopods, or molluscs
(Briggs et al., 1994). Dinomischus (Fig. 3.1B, 17) poses similar problems.
The bodies of these 10-cm-long animals consisted of a calyx, which housed
the mouth and anus opening onto the upper surface of the calyx, and a
stem, which was anchored in the sediment (Briggs et al., 1994). These
animals have been compared with both echinoderms and entoprocts, but
their taxonomic affinities are presently unclear. Continued study and the
discovery of new fossils will likely resolve their positions.
COMPARATIVE APPROACHES
Comparative biologists use two very different approaches in for-
mulating evolutionary statements: cladistics (or phylogenetics) (Hennig,
1966; Wiley and Lieberman, 2011) and phenetics (Sokal and Sneath, 1963;
Sneath and Sokal, 1973). Both involve comparing traits or characters (any
definable attribute of an organism) among multiple species, but each
treats similar characters differently. Cladists, following Hennig (1966),
divide similar characters among organisms into three categories: shared
primitive characters, shared derived characters, and uniquely derived
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Evolution of Centralized Nervous Systems / 45
characters. Furthermore, cladists hold that only shared derived characters,
which they define as phylogenetic or taxic homologs (Patterson, 1982), can
form the basis for establishing genealogical relationships. Such relation-
ships are usually illustrated as a dendrogram or a sequence of branches
(a cladogram). In contrast, phenetists say that overall similarities define
homologies, which can be recognized by structural and compositional
correspondence and are said to be phenetic or operational homologies
(Sneath and Sokal, 1973). Phenetists also believe that genealogical related-
ness depends on the degree of similarity (i.e., the number of operational
homologies) shared by a group of organisms.
In most groups of organisms, multiple hypotheses of genealogical
relationships can be proposed. Hennig (1966) was the first to discover
that these hypotheses can be evaluated objectively by grouping organisms
based on shared derived characters. For example, given three taxa—A, B,
and C—there are only three possible hypotheses regarding their related-
ness: A is more closely related to B; A is more closely related to C; or A, B,
and C are equally related. Because phylogeny is a historical process that
has occurred only one time, only one of these hypotheses can be valid. The
distribution of postulated shared derived characters will indicate the valid
hypothesis. That is, the genealogical hypothesis that reveals the largest
number of shared derived characters and thus requires the fewest inde-
pendent origins is the one that is supported. (This conclusion was initially
based on simple parsimony but has been recently supported by sophis-
ticated algorithms, such as Bayesian inference.) In rejecting the alternate
genealogical hypotheses, their “shared derived characters” are revealed
to be shared primitive characters or homoplasies (Wiley and Lieberman,
2011). This finding does not mean that such characters are of no phylo-
genetic interest. Many shared primitive characters are, in fact, shared
derived characters at some lower level of the tree of life and thus linked as
transformational homologs to shared derived characters at a higher level.
In addition, analysis of homoplasious characters can reveal structural and
functional constraints in phylogeny. Although transformational homolo-
gies do not specifically define taxonomic groups, they become critical in
evaluating the phylogenetic history of characters across clades. Hennig
(1966) also discovered that character polarity (i.e., primitive or derived)
could be determined by an outgroup rule, which proposes that, when
two or more homologous characters occur within a group, the character
outside the group is the primitive character, whereas the character found
only within the group is the derived character. Realization of the predic-
tive power of the outgroup rule in the work by Hennig (1966) has given
rise to a wide range of evolutionary studies that have attempted to recon-
struct the phylogenetic history of molecular characters (Halanych and
Passamaneck, 2001), morphological characters (Northcutt, 1984; Butler,
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1994; Striedter, 1997), behavioral and ecological characters (Krubitzer et al.,
2011), and biogeographical events (Grande and Bemis, 1998). Such studies
are usually called cladistic studies, because they rely on the outgroup rule
in the work by Hennig (1966), although they deal with the phylogeny of
a character rather than reconstructing the phylogenetic history of taxa.
It has been claimed that studies involving the outgroup rule in the work
by Hennig (1966) in this way are not truly cladistic analyses (Strausfeld,
2012), presumably because they rely on cladograms generated in other
studies; however, there is a general consensus that they do fall under the
rubric of cladistic methodology (Nieuwenhuys et al., 1998; Striedter, 2005).
Because of its logic and methodological transparency, cladistics has
largely replaced phenetics in zoological systematics, except at the species
level, and much of its methodology is widely used to analyze the phylo-
genetic history of both genotypic and phenotypic characters. The phenetic
approach is still widely used, however, in developmental genetic studies,
in which evolutionary statements are based on a two-taxon approach, pos-
sibly because until recently, it has been difficult to explore the genetic basis
of phenotypic characters widely among different taxa. The roles of both
cladistic and phenetic approaches are examined in the next three sections
dealing with the molecular clock hypothesis, the genetic basis of bilaterian
body plans, and an outgroup analysis of metazoan neural characters.
Molecular Clock Hypothesis
Evolutionary biologists seek to date the origin of metazoan clades
and determine the rate at which they evolve. Initially, clade origins were
based solely on the earliest occurrence in the fossil record of that clade,
and the temporal rate was established by current rates of sedimenta-
tion and, subsequently, radiometric dating (Benton et al., 2009). Given
the incompleteness of the fossil record, however, the accuracy of these
estimates of origin and tempo were open to question. In the early 1960s,
it was discovered that differences between lineages in the number of
amino acids in several proteins seemed to be roughly linear in time and
that evolutionary changes in these proteins, as well as in genes, could be
used to infer the separation in time of different lineages (Zuckerkandl and
Pauling, 1962; Margoliash, 1963; Kumar, 2005). This discovery led to the
neutral theory of molecular evolution, which claimed that most changes in
proteins and genes would be neutral and that fixation of these molecules
would accumulate at a clock-like rate (Kimura, 1968). It has become clear,
however, that the rate of change in different molecules in different clades
varies tremendously (Ayala, 1986, 1997; Rodríguez-Trelles et al., 2004).
This problem has been addressed by modeling relaxed molecular clocks,
in which mean rates of sequence divergence for each molecule have been
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Evolution of Centralized Nervous Systems / 47
calculated (Wray et al., 1996) or the molecular clock is calibrated by one or
more points based on fossil dates (Benton et al., 2009). Relaxed molecular
clocks are frequently generated in a two-step process: the most supported
cladogram is generated by cladistic analysis of the molecules of interest,
and then, a clock is calibrated by using the time of origin of several clades
based on the fossil record.
Conclusions based on mean rates of sequence divergence differ
greatly from those conclusions based on multiple fossil calibration points
in regard to the time of origin for metazoan clades. Using mean rates of
sequence divergence, the origin and divergence of bilaterians has been
placed at ~1.0–1.2 billion years ago (Wray et al., 1996). In contrast, fossil-
calibrated molecular clocks place the origin and divergence of bilaterians
at ~700–600 Mya (Bromham et al., 1998; Douzery et al., 2004; Peterson
et al., 2004; Peterson and Butterfield, 2005; Erwin et al., 2011). These
later dates suggest that, although animals arose during the Cryogenian
Period (~850–635 Mya), bilaterians arose and began to radiate during the
Ediacaran Period.
Genetic Basis of Bilaterian Body Plan
In the last 20 years, developmental biologists have made spectacu-
lar strides in revealing the genetic basis of the regulatory networks that
underlie anterior–posterior and dorsoventral patterning of body organi-
zation in many bilaterian metazoans (Lewis, 1978; Nüsslein-Volhard and
Wieschaus, 1980; Bopp et al., 1986; Cohen and Jürgens, 1990; McGinnis
and Krumlauf, 1992; Holley et al., 1995). Anterior–posterior patterning
involves a homeobox gene superfamily in which orthodenticle and its
paralogue (Otx) are expressed in the rostral head, followed more caudally
by the expression of paired-box (Pax) genes and most caudally by Hox
genes, which continue to be expressed in the trunk. Much early work on
body patterning was based on two taxon comparisons involving fruit
flies and mice, but this research has now included extensive outgroup
analyses (Noll, 1993; Finnerty and Martindale, 1998; Nederbragt et al.,
2002; Holland and Takahashi, 2005).
One consequence of the discovery of the genetic basis of anterior–
posterior body patterning in bilaterian metazoans was the realization
that Otx, Pax, and Hox genes are also expressed in a rostral to caudal
sequence in those bilaterians that possess brains (Reichert and Simeone,
2001; Hirth et al., 2003; Denes et al., 2007; Arendt et al., 2008; Hirth, 2010).
This finding gave rise to the tripartite brain hypothesis, which proposes
that there is a monophyletic origin of the brain in bilaterians. The origi-
nal hypothesis (Hirth et al., 2003) was based on a two-taxon comparison
(between an arthropod and chordates), but more recently, this hypothesis
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was extended to a rudimentary three-taxon outgroup analysis (Arendt et
al., 2008) involving an annelid (a spiralian protostome), an arthropod (an
ecdysozoan protostome), and a mammal (a deuterostome). To date, how-
ever, there has been no attempt to polarize expression of these homeobox
genes in ecdysozoan or spiralian protostomes, which possess less complex
CNSs, although a tripartite brain in deuterostomes has traditionally been
interpreted as a derived character (Nieuwenhuys et al., 1998; Striedter,
2005). Hopefully, continued study of the genetic regulatory networks
underlying anterior–posterior patterning in ecdysozoan and spiralian
protostomes will provide additional insights into the phylogeny of these
networks and brain evolution in bilaterians.
The discovery of the genetic processes involved in the dorsoven-
tral patterning of the body in several bilaterian metazoans (Holley et
al., 1995; De Robertis and Sasai, 1996; Arendt and Nübler-Jung, 1997)
may also provide support for the tripartite brain hypothesis. It has been
shown that the gene short gastrulation (sog) in Drosophila is functionally
homologous to the gene chordin (chd) in Xenopus; both promote dorsal
development, whereas the gene decapentapelgic (dpp) in Drosophila and its
homolog bmp-4 in vertebrates promote ventral development (Holley et
al., 1995). Both sog and chd, in conjunction with other genes, also promote
formation of neurogenic ectoderm. However, the expression of sog and
chd are inverted in the blastula of Xenopus relative to their expression in
stage 12 embryos of Drosophila. This finding leads to the suggestion that
vertebrates evolved from protostomes by a dorsoventral inversion (De
Robertis and Sasai, 1996; Arendt and Nübler-Jung, 1997), resurrecting
an earlier inversion hypothesis proposed in the work by Geoffroy Saint-
Hilaire (1830). If a dorsoventral inversion of the body axis occurred with
the origin of chordates, then their brains could be considered homologous
(De Robertis and Sasai, 1996; Arendt and Nübler-Jung, 1997; Reichert
and Simeone, 2001). Once again, this claim is based on a two-taxon phe-
netic comparison and not a cladistic one. Work on body patterning in an
enteropneust hemichordate Saccoglossus, which has a diffuse nerve net,
reveals the same expression of homeobox genes in the anterior–posterior
body axis as in other bilaterians, but the antagonistic actions of sog and
dpp do not restrict neural development to the dorsal body surface of this
bilaterian (Lowe et al., 2003; Lowe, 2008). This finding suggests that,
although the genetic signaling network is homologous between proto-
stomes and deuterostomes, this network can be deployed to regulate the
development of fundamentally different nervous systems. It is possible
that the ancestral roles of the regulatory networks involved in anterior–
posterior as well as dorsoventral patterning did not extend to patterning
CNSs and that elements of these networks were subsequently co-opted
in neural development.
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Evolution of Centralized Nervous Systems / 49
Outgroup Analysis of Metazoan Central Neural Characters
Clearly, it is difficult to discern the connection between genetic net-
works and phenotypic characters (Conway Morris, 2000a; Wagner, 2007).
This discernment will become easier as the phylogeny of particular genetic
networks is mapped cladistically, with particular attention paid to taxa
that occupy critical positions in the metazoan cladogram. Meanwhile, it is
useful to conduct an outgroup analysis of the distribution of central neu-
ral characters in extant bilaterians. Although we recognize ~40 metazoan
phyla, comprising some 1.3 million described species (Edgecombe et al.,
2011), only 8 of these phyla (cnidarians, platyhelminthes, annelids, mol-
luscs, nematodes, arthropods, echinoderms, and chordates) comprise 99%
of extant metazoan species, and 4 of these phyla (annelids, some molluscs,
arthropods, and chordates) have brains; thus, bilaterian metazoans with
brains comprise 90% of the extant metazoan species. Clearly, the evolu-
tion of a brain as part of an adaptive suite has been under heavy selective
pressure. If an outgroup analysis of central neural characters reveals that a
brain is a shared primitive character for bilaterians, then the tripartite brain
hypothesis might be supported. This finding would be the case, however,
only if a brain divided into three parts is a shared primitive character. If
tripartite brains are revealed to be a derived neural character, then this find-
ing would be evidence again for the tripartite brain hypothesis. If brains
are revealed to be a derived character, then brains in bilaterians must have
evolved a number of times independently, which suggests that elements
of the genetic network underlying anterior–posterior patterning have also
been co-opted for brain patterning a number of times independently.
An outgroup analysis of central neural characters in metazoans is
complicated by the lack of a consensus regarding a single metazoan
cladogram (Adoutte et al., 2000; Glenner et al., 2004; Hejnol et al., 2009;
Edgecombe et al., 2011; Erwin et al., 2011) and difficulties in defining
distinct central neural characters. Despite these difficulties, comparative
molecular studies have clarified much of the phylogeny. All molecular
studies recognize bilaterians as a monophyletic taxon divided into two
major clades: the protostomes and the deuterostomes (Fig. 3.2). Further-
more, the protostomes can be divided into two superphyla or clades
termed the ecdysozoans and the spiralians (lophotrochozoans). Conflicts
regarding metazoan phylogeny currently center on the contentious rela-
tionships of acoelomorph flatworms (Acoela and Nemertodermatida), the
genus Xenoturbella (a small ciliated marine worm), and the basal metazoan
clades (cnidarians, ctenophores, placozoans, and poriferans). The clado-
gram generated in the work by Glenner et al. (2004) was chosen for the
present outgroup analysis (with some modifications), because it is the only
Bayesian phylogenetic analysis that includes both molecular and morpho-
logical data. The Acoela group has been interpreted as the sister group
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50 / R. Glenn Northcutt
FIGURE 3.2 Outgroup analysis of cephalic neural characters across extant meta-
zoans. The cladogram is modified from the work by Glenner et al. (2004), with the
inclusion of xenacoelmorphs as the sister taxon to other deuterostomes (Philippe
et al., 2011). The analysis indicates that the last bilaterian common ancestor pos-
sessed a diffuse nerve plexus and that brains independently evolved at least four
times among bilaterians.
to all other bilaterians (Glenner et al., 2004) or a deuterostome clade, the
xenocoelmorphs (Hejnol et al., 2009; Philippe et al., 2011), which includes
acoelomorph flatworms, nemertodermatids, and Xenoturbella. When xena-
coelmorphs are interpreted as deuterostomes, they are considered either
as the sister group to Ambulacraria (Echinodermata and Hemichordata)
or the sister group to all other deuterostomes (Perseke et al., 2007). The
latter interpretation is accepted in the present outgroup analysis. The fol-
lowing characters—or levels of increasing morphological and functional
complexity in the cephalic CNSs of extant metazoans—are recognized
in the present outgroup analysis: (i) diffuse nerve nets or subepidermal
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Evolution of Centralized Nervous Systems / 51
nerve plexuses; (ii) simple cerebral ganglia; and (iii) brains, defined as a
central collection of neural centers, with distributed and hierarchical func-
tions. A considerable range of morphological complexity occurs within
each of these cephalic neural characters (Bullock and Horridge, 1965).
Diffuse nerve nets range from those nets of cnidarians and ctenophores
to those nets in enteropneust hemichordates, in which neural cell bodies
occupy a subepidermal nerve plexus with centralized bundles of fast-
conducting axons forming dorsal and ventral nerve cords. Cerebral gan-
glia range from simple, bilobed ganglia in polyclade flatworms to more
complex multiple cephalic ganglia in many gastropod molluscs (Bullock
and Horridge, 1965). In most annelids, arthropods, and some cephalopod
molluscs, brains form by elaboration of one or more cephalic ganglia,
whereas in vertebrates, they form by elaboration of their dorsal hollow
neural tube. Categorizing cephalic nervous systems in protostomal bilat-
erians as simple cerebral ganglia or brains is somewhat arbitrary, because
the criteria are based on the relative size and functional complexity of
the cephalic structure in question. Simple cerebral ganglia and brains in
protostome bilaterians thus represent grades of increasing morphologi-
cal and functional complexity. There is a similar problem in defining a
“brain” among chordates: cephalochordates possess a brain that is only
slightly more complex than their spinal cord; they do not seem to have a
homolog of the cerebrum in vertebrates; and separation of a thalamus and
midbrain does not appear to exist, nor does a cerebellum (Nieuwenhuys
et al., 1998; Northcutt, 2003). It is possible that future analyses will reveal
additional morphological categories among cephalic neural characteristics
in metazoans; if so, this information may help to resolve the definition
of a brain and thus contribute to our understanding of the evolution of
centralized nervous systems.
Distribution of the three cephalic neural characters is plotted on the
cladogram in Fig. 3.2. Polarization of these characters among deutero-
stomes suggests that a diffuse nerve plexus is the primitive character, and
a brain is the derived character. In both ecdysozoan and spiralian clades,
simple cerebral ganglia seem to be the primitive character, whereas a brain
is the derived character. If so, brains have evolved three times indepen-
dently among protostome bilaterians (Fig. 3.2). The condition in the last
bilaterian common ancestor could be either a diffuse nerve plexus or a
simple cerebral ganglion, but examination of the metazoan outgroups sug-
gests that the last bilaterian common ancestor possessed a diffuse nerve
plexus like the last common ancestor of all metazoans.
Different conclusions might be reached, however, if xenocoelmorphs
were determined not to be deuterostomes (Philippe et al., 2011) but the
sister group to all other bilaterians (Adoutte et al., 2000). If this finding
was the case, it would be impossible to polarize the characters diffuse
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52 / R. Glenn Northcutt
nerve plexus and brain in deuterostomes. Because the third neural char-
acter, simple cerebral ganglion, is the primitive condition in protostome
bilaterians, additional examination of the outgroups, xenocoelmorphs
and the basal metazoan clades, would still indicate that the last common
bilaterian ancestor and the last common metazoan ancestor possessed a
diffuse nerve plexus.
Outgroup analysis of intracladal variation in central cephalic neural
characters also indicates that brains have evolved numerous times inde-
pendently. For example, analysis of cephalic neural characters within the
molluscan clade reveals that basal molluscans (monoplacophorians and
polyplacophorians) have simple cerebral, pleural, and pedal ganglia inter-
connected by ventral and lateral medullar cords (Bullock and Horridge,
1965), which are retained in some basal gastropods. Hypertrophy of the
various ganglia seems to have occurred independently in several gastro-
pod groups as well as independently in octopod cephalopods (Moroz,
2009), which have evolved the most complex brains among invertebrates.
It could be said that the present outgroup analysis may be flawed by
mistaking secondary character reductions (degenerative events) for primi-
tive characters (Reichert and Simeone, 2001; Jenner, 2004; Hirth, 2010). If
this flaw was the case, 23 of ~30 phyla would have to possess secondarily
degenerated cephalic neural characters, which in the context of this clado-
gram, would have to have occurred at least 11 times independently. Need-
less to say, this interpretation would not be parsimonious, but it does raise
the question of how secondarily simplified characters can be recognized
from primitive simple characters.
In addition to the outgroup rule, there are at least four auxiliary cri-
teria that suggest to zoologists that primitive characters are actually sec-
ondarily simplified characters: (i) when the characters are in sessile taxa,
(ii) when the characters are in parasitic taxa, (iii) when the characters are in
paedomorphic taxa, and (iv) when the characters are in taxa with second-
ary loss of microRNAs. Three of these criteria have been recognized by
zoologists for almost 50 years (Bullock and Horridge, 1965). Secondarily
simplified characters have long been suspected in sessile tunicate urochor-
dates, bryozoans, phoronids, entoprocts, and parasitic cestode and trema-
tode flatworms and rhombozoans, which are obligate symbiotes in the
nephridia of cephalopod molluscs. Similar secondary simplification also
frequently occurs when ancestral ontogenies are truncated (paedomor-
phosis), leading to reduction in body size and morphological complexity,
which is widely documented in salamanders (Duellman and Trueb, 1986).
The fourth criterion, taxa with secondary loss of microRNAs, may offer a
molecular explanation for the first three criteria, and it may also identify
additional taxa characterized by multiple character reductions or losses.
Acoela, Platyhelminthes, and Xenoturbella each seem to have secondarily
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Evolution of Centralized Nervous Systems / 53
lost microRNAs (Erwin et al., 2011), which suggests that many of their
morphological characters are secondarily simplified. It should be noted
that, in most if not all of the taxa said to possess secondarily simplified
characters, these characters are widespread throughout most organ sys-
tems in that taxon rather than confined to a single system. Furthermore,
the fossil record can be of immense value in polarizing life histories when
the earliest members of a clade are vagile and shift to a sessile existence
or when there are clear trends in body size.
LAST COMMON BILATERIAN ANCESTOR
There are two very different reconstructions of the morphology of
the last common bilaterian ancestor (LCBA) or urbilaterian (De Robertis
and Sasai, 1996). Many developmental biologists, relying on the roles of
numerous genes and gene networks in the development of arthropods and
vertebrates [summarized in Erwin (2006)], suggest that the LCBA was a
morphologically complex organism with anterior–posterior differentia-
tion of a head that possessed paired eyes, a tripartite brain, and a seg-
mented trunk with a differentiated gut, heart, and appendages. In contrast,
many paleontologists and zoologists would suggest that the LCBA was far
simpler morphologically, perhaps a small vernanimalcular-like organism
that was patterned in both the anterior–posterior and dorsoventral axes
but not segmented. This ancestor would have possessed a mouth and
anus connecting a differentiated gut surrounded by coelomic cavities. The
nervous system would have been a diffuse nerve plexus, and the apical
pole of the organism would have had simple ocelli composed of both
ciliary and rhapdomeric photoreceptors. The trunk may have contained
contractile muscle cells but no heart, segmented muscles, or appendages,
and locomotion would primarily have involved ciliary gliding.
Both molecular clock and paleontological data indicate that bilaterian
metazoans arose ~600–700 Mya during the Ediacaran, and they radiated
rapidly into most bilaterian crown clades by the end of the Cambrian
(Erwin et al., 2011). It is also clear that most genes involved in develop-
mental genetic networks determining anterior–posterior and dorsoventral
patterning must already have been in place in the LCBA (Davidson, 2006;
Erwin et al., 2011). If the fossils of the Doushantuo Vernanimalcula and
some of the macroscopic fossils of the Ediacaran biota, such as Dickinsonia
and Kimberella, are interpreted as stem bilaterians, then the body plans of
the earliest bilaterians must have been relatively simple and comparable
with the body plans of living placozoans, platyhelminthines, and apla-
cophoran molluscs. Although neural structures are rarely fossilized, it is
possible to relate neural complexity to specific grades of body complexity
(Bullock and Horridge, 1965). A conservative interpretation of body com-
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54 / R. Glenn Northcutt
plexity of the macroscopic Ediacaran biota suggests that these organisms
were characterized by diffuse nerve plexuses. A more heterodox inter-
pretation of organisms, such as Spriggina, Praecambridium, and so-called
soft-bodied “trilobites,” is that they are members of clades closely related
to annelids and arthropods, which would suggest that some Ediacaran
organisms may have already evolved cerebral ganglia sufficiently complex
to be termed brains. Given the body complexity of Cambrian annelids,
arthropods, and chordates, it is reasonable to assume that the CNSs in
these clades were characterized by brains. Interestingly, this level of neural
complexity may not have been reached by cephalopod molluscans until
the Devonian some 70 Myr later, with the origin of octopod cephalopods
(Kluessendorf and Doyle, 2000).
Outgroup analysis of inter- and intraclade variations in cephalic neural
characters (Fig. 3.2) supports an LCBA model with a diffuse nerve plexus,
which subsequently coalesced into a number of cephalic ganglia and nerve
cords or a dorsal hollow neural tube. Hypertrophy and increase in cellular
differentiation of cephalic ganglionated and dorsal neural tube systems
independently reached levels of neural complexity that are defined as
brains in arthropods, annelids, and some molluscs and chordates.
Conservation of genetic regulatory networks, which has been termed
deep homology (Shubin et al., 2009; Scotland, 2010), has been invoked to
claim that all bilaterian brains are homologous (a shared derived char-
acter of all bilaterian metazoans) and consist of three anterior–posterior
divisions (tripartite brain hypothesis). A basic assumption of this claim is
that conserved genetic regulatory networks also have a conserved role in
the development of phenotypes. As developmental biologists dissect the
genetic mechanisms that control processes underlying the development
of phenotypic characters, it seems that some genetic networks determine
character identity, whereas others determine character state (Wagner,
2007). Only as the genomes of additional taxa are probed and analyzed
cladistically will it be possible to determine if homologous character
identity networks underlie phenotypically recognized brain divisions
across all bilaterian metazoans. Meanwhile, metazoan interrelationships
and the evolution of their nervous systems will continue to be debated,
hopefully, with the reminder by the late renowned invertebrate zoologist,
Donald P. Abbott, to “[c]ultivate a suspicious attitude toward people who
do phylogeny” (Brusca and Brusca, 2003).
ACKNOWLEDGMENTS
This paper is dedicated to the memory of Theodore H. Bullock, whose
encyclopedic knowledge and boundless enthusiasm defined the study of
brain evolution for a generation and greatly informed my thinking, and
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Evolution of Centralized Nervous Systems / 55
the memory of Sue Commerford, a good friend and superb assistant until
her death during the preparation of this manuscript. I thank Jo Griffith
for assistance with the illustrations and Mary Sue Northcutt for help with
many phases of the research and manuscript preparation. This work was
supported by National Science Foundation Grant IBN-0919077 and private
funding.
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