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The neural crest is an embryonic population of migratory multi-potent cells of invertebrate innovation. These cells can form numerous derivatives, including cranio-facial bone and cartilage. The formation of such structures resulted in early vertebrates transitioning from filter feeders to active predators, a major step in evolutionary terms. These reasons are why the evolutionary origin of the neural crest is of interest to biologists. In this review the formation and development of the neural crest and NCCs is summarised, possible evolutionary origins are examined with particular reference to the gene regulatory network as well as insights obtained from research on ascidians, lampreys and amphioxus. Overall the aim of this review is to summarise the current opinion of the evolutionary origins of the neural crest.
1.1 Neural crest and neural crest cells
The neural crest is a migratory, multi-potent embryonic cell population that is traditionally a characteristic unique to all vertebrates. Neural crest cells (NCCs) can differentiate into a diverse array of cell types and form multiple derivatives including melanocytes, glia and the sensory neurons. In the vertebrate head NCCs can form craniofacial bone and cartilage as well as smooth muscle cells, amoung other structures.
The structures formed from the neural crest, are basically those that distinguish vertebrates from their close relatives. Some of the structures derived from the neural crest, such as the jaw and sensory ganglia enabled early vertebrates to alter their feeding habits (Gans & Northcutt, 1983, Northcutt & Gans, 1983), basically switching from being filter feeders to active predators, a major evolutionary stepping stone.
1.2 Formation and development of the neural crest and neural crest cells
NCCs first appear when they detach from the dorsal aspect of the neural tube. Before this appearance, the neural crest and neural tube are formed during the process of neurulation. The formation of the Neural tube (Fig. 1) is an important step during neurulation as it is the precursor of the central nervous system. At the beginning of the process of neurulation the neural folds (from which the neural crest is derived) are located on either side of the neural plate, separating the neural plate from the non-neural ectoderm. As the neural plate invaginates to form the neural tube, the neural folds converge and fuse to form the neural crest whilst separating from the epidermal ectoderm. At this stage the neural crest is located on the dorsal aspect of the neural tube.
The process of induction is regulated by Bmp signalling, namely Bmp-4 and Bmp-7. Another signalling molecule, Wnt plays a role in the induction process, aside from the anterior-posterior patterning in the embryo (Morales et al, 2005, Raible & Ragland, 2005). Noggin (expressed in the dorsal mesoderm) is thought to also play a role in induction (Mayor et al. 1997)
Once induction is complete, the NCCs must detach from the neural tube. For this to occur the NCCs must undergo the process of delamination. Before the process of delamination the NCCs transition from epithelial type cells to mesenchymal type cells (Ahlstrom & Erickson, 2009). A summary of the genetic pathways, from induction to the transition from epithelial type cells to mesenchymal type cells can be seen in Fig. 2.
This involves an alteration in the concentration of cell adhesion molecules expressed by the NCCs. The delamination process is regulated by Bmps signalling, most prominently Bmp-6. A binding protein called Noggin acts as an inhibitor to Bmp. During the delamination process signals from the somite down regulate the expression of noggin so that it no longer inhibits Bmp (Morales et al, 2005, Raible & Ragland, 2005)
1.3 Migration and Derivatives of the neural crest cells
Once the NCCs detach from the neural tube, they migrate along predefined pathways to various sites around the embryo, where they differentiate into a variety of cell types. The main derivatives are shown in Fig. 3.
The neural crest can be divided into four different regions depending on the location of the neural crest. These regions are the cranial neural crest, the vagal and sacral neural crest, the cardiac neural crest and the trunk neural crest (locations are illustrated in Fig. 4). The migratory pathway and the derivatives formed differ between regions.
The cranial neural crest:
Cranial NCCs migrate dorsolaterally. They enter the pharyngeal arches and form structures including the bones of the middle ear and jaw. Cranial NNCs differentiate into cranio-facial bone, cartilage, muscle and connective tissue. (Gilbert SF, 2000, Kulesa et al, 2010, Kulesa &Gammill, 2010)
The vagal and sacral neural crest:
The vagal and sacral NCCs form the parasympathetic ganglia of the gut. (Gilbert SF, 2000. Le Douarin & Teillet, 1973, Pomeranz et al, 1991)
The cardiac neural crest:
The cardiac neural crest forms the musculoconnective tissue wall (found in the arteries) as well as part of the septum (Gilbert SF, 2000).
The trunk neural crest:
The trunk neural crest have two migratory pathways. The first pathway is for the NNCs that transition to melanocytes. These cells migrate dorsolaterally towards the ventral midline of the stomach. For second migratory pathway, the NCCs migrate ventrolaterally to the sclerotomes. Some NCCs will remain in the sclerotome and produce the dorsal root ganglia. The rest of the NCCs will migrate ventrally and form the sympathetic ganglia and other structures. (Gilbert SF, 2000, Kulesa et al, 2010, Kulesa &Gammill, 2010)
2: Evolutionary Origin of the Neural Crest
2.1 Evolutionary Origin and the Gene Regulatory Network
Comparing and contrasting the gene regulatory networks of the chordata:
In this review the gene regulatory network is going to be used in order to obtain an insight into the evolutionary origin of the neural crest. To do this the neural crest gene regulatory network of the vertebrates (gnathostomes) will be compared and contrasted with the gene regulatory networks of the lamprey, the amphioxus and the ascidian as well as other aspects in relation to these three models. The phylogenetic relationship (hypothesized) is shown in Fig. 5.
The neural crest gene regulatory network regulates the developmental processes of the neural crest. The network regulates the complex processes, from induction to migration towards differential sites (Fig. 6).
The gene regulatory network can be divided into 4 sub-networks. These networks are the border induction signals, the neural plate border specifiers, the neural crest specifiers and the neural crest effector genes.
Border Induction Signals:
Signalling molecules that are secreted by the epidermis and mesoderm. These molecules cause the non-neural ectoderm to separate from the neural plate during neural induction. Some examples are Fgf, Bmp and Wnt.
Neural plate border specifiers:
Set of transcription factors that establish the neural plate border. Some examples are Zic, Msx, Pax3/7 and Dlx.
Neural crest specifiers:
These genes are activated by NCCs. Each specifier is important as the cross regulate and activate specific downstream effector genes. Some examples are AP2, SoxE, Snail, FoxD3, Id, cMyc and Twist. Twist and Id being transcription factors.
Neural crest effector genes:
Neural crest effector genes activate the expression of effector gene. This results in the appearance of such properties as migration. Some examples include Col2a, Mitf, Trp and cRet.
Fig. 7 shows an evolutionary summary of the neural crest gene regulatory network (GRN).
Lamprey as a model:
Lampreys are part of the agnathans (jawless) and represent the most primitive of the cyclostomes. Lampreys can be described as "Living Fossils", in that they reflect the condition of primitive vertebrates. Because they possess characteristics similar to those of the common ancestor, they possess a network that is also similar to the ancestor. The lamprey is a basal vertebrate and as such possesses a bona fide neural crest, although the lamprey does lack some neural crest derivatives, such as the sympathetic chain ganglia. The formation of the neural tube also differs from that of a jawed vertebrate as in the lamprey the neural tube forms by a secondary cavitation of the neural keel. (Sauka - Spengler & Bronner - Fraser, 2008). The neural crest gene regulatory networkof the lamprey compared to that of the gnathostomes is shown in Fig. 8.
Border Induction Signals:
The expression of the signalling molecules, including Bmp and Wnt, show a similar sequence to that of the jawed vertebrates during early neural crest formation (Sauka - Spengler & Bronner - Fraser, 2008, Sauka - Spengler et al, 2007, Nikitina et al, 2008).
Neural plate border specifiers:
When the neural plate border specifiers MsxA, ZicA and Pas3/7 are deactivated, there is a depletion in the expression of the neural crest specifiers. This is a similar occurance ti that which is observed in the jawed vertebrate when the same neural plate border specifiers are deactivated. Inhibition of the neural plate border specifiers results in defects being observed in the migratory and post-migratory neural crest, as well as defects also presenting in the derivatives of the neural crest and in associated structures. From the results obtained, Sauka - Spengler put forward that "the more proximal modules of the neural crest gene regulatory network are highly conserved amoung jawless and jawed vertebrates" (Sauka - Spengler & Bronner - Fraser, 2008, Sauka - Spengler et al, 2007, Nikitina et al, 2008).
Neural crest specifiers:
In jawed vertebrates, the expression of Twist and Etsl is present in the first neural crest progenitors. However in the lamprey, they are expressed in the migratory cranial neural crest only. In the jawed vertebrates, the transcription factors Twist and Etsl possess important roles in the specification of neural crest cell progenitors. In the lamprey, they are isolated to the cranial neural crest, a single lineage. There are two possabilities for why this is. First, both twist and Etsl were co-opted to an earlier function of the lineage, or secondly, in relation to the lamprey they lost their earlier function (Sauka - Spengler & Bronner - Fraser, 2008, Sauka - Spengler et al, 2007, Nikitina et al, 2008)
Neural crest effector genes:
There are some notable differences in the expression of downstream neural crest effector genes compared to that of the jawed vertebrate. As stated before neural crest effector genes control the migratory preparedness and multipotency of the neural crest. As expected there are to be differences noted in the timing and location between species, but there are generally still similarities present (Sauka - Spengler & Bronner - Fraser, 2008, Sauka - Spengler et al, 2007, Nikitina et al, 2008)
Id expression in Lamprey
In Meulemans et al (2003), they found that the gene cooption of Id occurred at an early stage in the vertebrate lineage.
Amphioxus as a model:
Amphioxus (Fig. 9) belongs to the sub-phylum Cephalochordata. On the outside the amphioxus resembles the vertebrates, but it lacks a number of vertebrate characteristics, such as the neural crest. (Nikitina, 2009)
In amphioxus the formation of the neural tube (Fig. 10) differs from the processes discussed previously. During neurulation the ectoderm covers the neural plate, then condenses to form the neural tube (Yu, 2010).
Putative neural border gene network in amphioxus:
The putative neural border gene network is illustrated in Fig. 11.
Dorsal ectoderm patterening is conserved between vertebrates and cephalochordate.
Neural border specification is conserved between vertebrates and cephalochordate.
Pigment cell development is conserved in both vertebrates and amphioxus.
Amphioxus possesses a single neural crest specifier (lacks neural border expression).
Amphioxus is missing the sub-circuit that regulates delamination and migration. This is consistent with the absence of real neural crest cells. (Yu, 2010)
Id expression in Amphioxus
In Meulemans et al (2003), they found that the expression of the Id genes was not present in the lateral neural plate border and dorsal neural tube in relation to amphioxus. Id expression was present in these locations in relation to the vertebrates, as such they found that the Id expression in these locations was isolated to vertebrates. Because of this they believe that the evolution of the neural crest is progressed partially by cooption.
Ascidians as a model:
Ascidians belong to the Urochordates, a sister group of the vertebrates comprising of over 3000 species. Urochordates are commonly split into three classes, the ascidians, the larvaceans and the thaliaceans. The ascidians and the larvaceans both go through a complex life cycle (including a swimming larval stage). The process of neurulation in the ascidians is similar to that of the vertebrate during primary neurulation.
Neural Crest-Like Cells:
The ascidians were divided into four different groups depending on the level of complexity of the formation of the adult structures during adultation (Jeffery, 2007). He observed that it was the species that were less complex (ie. More similar to the vertebrates) that were being used mainly in embryological research. In Jeffery et al (2004) he used Ecteinascidia turbinate, This ascidian produced larvae of high complexity. During the research period Jeffery noted that a number of cells were detaching from the neural tube and migrating outwards, these cells were then differentiating into pigment cells. It was also noted that the cells were expressing neural crest markers. This type of cell became known as the neural crest-like cell.
In Jeffery (2006), he put forward the following argument in relation to the relationship between vertebrate neural crest cells and ascidian neural crest-like cells "the most striking similarity between vertebrate neural crest cells and ascidian neural crest-like cells is their mutual role in body pigment cell development. The origin of neural crest-like cells near the dorsal neural tube, migratory activity, and association with siphon primordia, probable ascidian placode homologues, also imply a close relationship between ascidian neural crest-like cells and vertebrate neural crest cells. Based on these similarities, we propose that the ascidian and vertebrate cells are homologous and had a common origin during chordate evolution"
This proposal was accepted by some (Donoghue et al ,2008, Jeffery, 2007) but others, still to this day, do not believe that there is enough evidence to prove that there is a homologous relationship between the NCCs and the NCLCs. It was proposed the neural crest cells could have been formed by convergent evolution (Nikitina et al, 2009).
In the study, Jeffery (2008), it was uncovered that the NCLCs used an alternative developmental mechanism for their migration as well as initiating differentiation. It is still unknown whether the NCLC area result of convergent evolution or not.
3.1 Gene Co-option and the Origin of the Neural Crest
Gene co-option is a concept that has come from the field of evo-devo. It can be defined as follows "a gene that has some initial well-established function in development becomes deployed, over the course of evolutionary time, to perform a new function - normally in addition to, rather than instead of, its original one" (Arthur, 2011). Gene co-option is the most probable method by which the neural crest may evolve (Menlemans & Bronner - Fraiser, 2005)
Origin of the neural crest:
There are two opinions as to when the evolutionary origin of the neural crest (Fig. 12). To add more data to this discussion Fig. 13 shows the comparison of the different networks, the vertebrate NC-GRN, the neural plate border GRN of amphioxus and the TLCN of ascidian, Ciona intestinalis.
One theory proposes that the neural crest appeared in a common ancestor of both the ascidians and the vertebrates and that the neural crest diversified further after the vertebrate and the urochordates split. For this theory to be correct, the neural crest-like cells would have to bona fide neural crest cells. However as stated previously, the probability of the neural crest-like cells being real, is unlikely due to the alternative mechanisms for migration and differentiation, but not impossible. The second theory is that the true neural crest may have formed after the vertebrate and urochordate split and that pre-prototypic neural crest formed before said split. It is possible that these precursor cells may have obtained a cell cycle regulatory mechanism which would have made it possible for the precursor cells to differentiate into new type of derivative and in the process become vertebrate neural crest.
I have attempted to use the regulatory networks of a numbers of diverse and unique models to better understand the vertebrate neural crest and obtain an insight into the evolution and origin of this embryonic cell population. With current research methods improving and interest in the multipotent neural crest cells growing, the answer to that question is just over the hill but it is a steep hill.