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= Neural Plate/Neural Border=
The patterning of the neural crest: its progenitor neural border domain and the pre-migratory neural crest cells.
Neural crest (NC) development starts in the ectodermal germ layer during early embryogenesis, more precisely during gastrulation, simultaneously with the events of neural induction. It continues throughout neurulation and organogenesis (Eames et al., 2020). Here we focus on the first steps of NC formation. The induction of the NC fate takes place in a specific region of the ectoderm known as the neural plate border or  better, the neural border, as part of this area is devoid of neural plate markers (NB/NPB). In the plane of the ectoderm, the NB is located between the non-neural ectoderm (prospective epidermis, positioned more laterally), and the neural plate (prospective CNS, positioned more medially). The NB ectoderm also lies above the paraxial and intermediate mesoderm (Alkobtawi et al., 2021; Milet and Monsoro-Burq, 2012). In addition, the NB ectoderm gives rise not only to NC cells but also to the cranial placodes (future sense organs), parts of the dorsal neural tube, and of the non-neural ectoderm (Schlosser, 2008).
Tissue interactions play an essential role during NB and NC induction. Thus, NB induction is regulated by coordinated activation of different signals secreted by the surrounding tissues: the non-neural ectoderm, the neural plate, and the underlying mesoderm.  The three main signaling pathways mediating these tissue interactions and ensuring the proper development of NC cells are the canonical Wnt/β-catenin signaling (WNT), the Bone Morphogenetic Protein (BMP), and Fibroblast Growth Factor (FGF) pathways. Multiple studies have shown that the activation of each of them is necessary but not sufficient alone and that they synergize to ensure appropriate levels of signaling targeted to the NB  (Garnett et al., 2012; Hong and Saint-Jeannet, 2007; Monsoro-Burq et al., 2005; Saint-Jeannet et al., 1997; Tribulo et al., 2003); reviewed in  (Prasad et al., 2019; Sutton et al., 2021).
Globally, during vertebrate gastrulation, graded BMP signaling specifies the mediolateral body axis while graded WNT and FGF signaling specify the anteroposterior axis of the neural plate, with no/low levels acting at the anteriormost part and higher levels for posterior trunk regions (reviewed in (Sutton et al., 2021). BMP signals are secreted by the nonneural ectoderm and the underlying lateral mesoderm to maintain the nonneural ectodermal fate and together with WNT signals repress the neural fate (Faure et al., 2002; García-Castro et al., 2002). In turn, the axial mesoderm and the medial part of the neural plate secrete diffusible BMP antagonists allowing the expression of neural genes thus creating a BMP signaling gradient (Plouhinec et al., 2013). Thereby, the current textbook model is that high BMP activity induces an epidermal fate, moderate BMP levels induce NB genes, whereas low BMP activity determines a neural fate and represses both NB and ectodermal fates (Brugger et al., 2004; Marchant et al., 1998; Schumacher et al., 2011; Suzuki et al., 1997). However, recent findings highlight the action of BMP signaling potentiators which act in the paraxial and intermediate mesoderm and in the NB ectoderm, ensuring a high level of BMP signaling rather than an intermediate one (Alkobtawi et al., 2021). At the same time, inductive WNT and FGF signals are involved in the formation of the NB. FGF ligands are secreted by the mesoderm, the sources of WNT ligands could vary according to the species, and include ectoderm and mesoderm (García-Castro et al., 2002; Monsoro-Burq et al., 2003). In addition, there are also several auxiliary signaling participating in NB induction, e.g. retinoic acid and hedgehog signaling (Tribulo et al., 2003), but these have not yet been fully integrated into the gene regulatory network governing NB induction.
The combination of WNT, BMP, and FGF pathways activates a complex network of transcription factors (TFs) within the neural border ectoderm, essential for NB induction and called the "NB specifiers". The most studied NB specifiers are Tfap2a, Gbx2, Msx1/2, Zic1, Pax3/7, and Hes4 (de Crozé et al., 2011; Monsoro-Burq et al., 2005; Sato et al., 2005; Simões-Costa and Bronner, 2015a). Once activated, the NB specifiers, along with extracellular signaling inputs (sustained or reactivated WNT signals for example),  trigger the expression of downstream "NC specifiers": the transcription factors that are essential for NC induction and its further development: TFAP2B, SNAI1/2, FOXD3, TWIST1, SoxE genes (SOX8/9/10). In addition, some NB specifiers such as TFAP2A also act reiteratively as NC specifiers, regardless of their previous role (de Crozé et al., 2011; Simões-Costa and Bronner, 2015b).
NC specifiers regulate NC induction of neural crest and further delamination of neural crest cells from neural tube via EMT but also activate downstream lineage-specific gene regulatory networks for the differentiation into distinct cell types. EMT is a process that is essential for the proper development of the neural crest and for the formation of many different tissue types. During EMT, cells undergo a series of changes that allow them to become more motile and migrate to different locations in the developing embryo. These changes include the loss of cell-cell adhesion, the acquisition of a more spindle-like shape, and the upregulation of various mesenchymal markers.
There are several transcription factors that are known to play a critical role in the preparation of the neural crest for EMT. These include Snai1 and Snai2, transcriptional repressors, that have been extensively studied in the context of neural crest specification and EMT. Overexpression of Snail1/2 has been shown to increase the size of the neural crest population, while their inhibition blocks neural crest specification and migration. The regulatory regions of Snail2 contain binding sites for LEF/TCF and Smad1, which are directly regulated by WNT and BMP signaling (Nieto, 2018; Vallin et al., 2001). In addition, Snail1 and Snail2 are direct targets of Zic1 and Pax3 during frog neurulation.o defects in the development of the craniofacial skeleton and pigmentation (Plouhinec et al., 2014).
Other transcription factors that have been implicated in the preparation of the neural crest for EMT include Twist1, which plays a role in the acquisition of a more spindle-like shape of the cells (Sepporta et al., 2022, p. 1). Twist1 directly interacts with the Snail1 and Snail2 proteins through its WR domain, and phosphorylation of Twist1 leads to the inhibition of the activity of Snail1 and Snail2 (Lander et al., 2013). Also, recent single-cell RNA sequencing data in mice and experimental manipulation of Twist1 expression in chick have demonstrated that Twist1 plays a role in regulating and promoting the mesenchymal fate choice (Soldatov et al., 2019).
Another essential for the specification and maintenance of the NC genes is the SOXE family of transcription factors, including Sox8/9/10. However, each factor has distinct functions within the NC gene regulatory network. In frog development, Sox8 and sox9 are among the first NC specifier genes to be expressed in the neural plate region, prior to the expression of Snai2 and Foxd3 (Hong and Saint-Jeannet, 2007; Spokony et al., 2002). Sox10, on the other hand, is expressed later in pre-migratory NC cells. Both So9 and Sox10 are activated by the canonical WNT signaling pathway, and the expression of Sox10 is controlled by Sox9 and Snai2 (Spokony et al., 2002).


Decades ago, Carl Gans and Glen Northcutt presented an intriguing ‘New head’ theory, which proposed that one of the significant inventions of vertebrates, in the evolutionary context is the development of a complex head [1]. This complexity conferred vertebrates with a plethora of novel cranial sensory organs and skeletal structures, contributing to an active predatory lifestyle and evolutionary success [1–3]. Various studies revealed that many of these novel cranial structures originate from two unique embryonic tissues: the cranial placodes and the neural crest (NC) [1,4,5]. While being ectodermal in origin, the neural crest and the cranial placodes give rise to multiple different tissues, with the neural crest also being able to form tissues of a mesodermal origin [Fig 1]. The cranial placodes develop into many of the paired sensory organs. In contrast, NC gives rise to various derivatives such as craniofacial bones and cartilage, melanocytes, and the peripheral nervous system.
The neural crest and the cranial placodes originate from the neural border, a strip of tissue positioned between the neural and non-neural ectoderm [6,8; Fig 2]. This tissue does not broadly express any specific transcription factors, but is demarcated by the overlapping expression of genes like Pax3, Zic1, Tfap2a, Dlx3, Msx1 and others. The relative expression levels of these major genes and differential activity levels of different signaling pathways lead to the differential fate specifications: high Wnt/low to intermediate BMP forms the neural crest while low Wnt/Low BMP forms the cranial placode progenitors. Although the timing of induction differs across species, the neural border gives rise to the neural crest and preplacodal ectoderm (progenitor to cranial placodes) between the end of gastrulation and the start of neurulation.
Due to the vast number of derivatives, defects in the neural crest or placodes during early embryonic stages can lead to multiple developmental disorders. The importance of NC development in humans can be exemplified by the fact that defects in the specification, migration and differentiation of NC cells result in an array of congenital disorders collectively known as neurocristopathies [12]. Neurocristopathies affect a considerable population of newborns resulting in various conditions such as cleft palate, Waardenburg syndrome, and Hirschsprung’s disease [12]. On the other hand, defective placodes lead to diseases such as Branchio-Oto-Renal (BOR) Syndrome. Understanding the signalling pathways and GRN that governs the specification of NC and placodes at the NB is critical for understanding the molecular mechanisms underlying neurocristopathies. Ultimately, investigating their specification at the molecular level will give more insight into the aetiology of such diseases and their better therapeutic management.
Various research studies and reviews have shed light on the development and derivatives of cranial placodes and the neural crest [3,6–8].
==Neural Crest Specification/PRE-EMT==
The neural crest is a fascinating population of transient multipotent and migratory cells exclusively acquired by vertebrates during evolution [8,9]. It was first observed more than 150 years ago (His, 1868). Over the years, intricate experiments by lots of scientists proved that the neural crest is indeed multipotent and although being ectodermal in nature, can give rise to mesenchymal tissues as well. Later, the identification of Slug (Snail2) gave the neural crest a distinct genetic identity (Nieto et al., 1994). The induction of neural crest from the anterio-lateral neural border occurs due to high Wnt signaling during the end of gastrulation (frog) or during early neurulation (chick). This is marked by the expression of certain neural crest-specific markers, such as Snail1/2, Sox8/9 and FoxD3. The neural crest can be classified into three different types depending upon its position relative to the body axis (and expression of hox genes) – the rostralmost cranial neural crest, the caudal trunk neural crest and the vagal neural crest in the middle. In most cases, the induction of the neural crest follows a rostral to caudal direction. The differentiation potential of the cranial and vagal neural crest is higher than the trunk neural crest, with derivatives of the former including both ectodermal and mesodermal tissues while derivatives of the latter are only ectodermal in nature. As neurulation progresses, we observe the expression of late neural crest genes like Sox10 and Twist1, which are required for maturation of the neural crest and EMT. As the neural folds meet and the neural tube closes, the neural crest cells start to migrate (rostral first) to their final destinations, where they will give rise to various derivatives such as the peripheral nervous system, craniofacial cartilage and bone, and melanocytes [9,10].
The formation of NC at the NB is a hierarchical process governed by various signalling pathways and a complex gene regulatory network (GRN) involving multiple genes and transcription factors (TFs) [6]. The first process in the NC formation is the establishment of NB by TFs, notably pax3, zic1, dlx3 and msx1, also termed as NB specifiers (or NB-TFs) [6]. The interaction of various inductive signalling molecules (BMP, Wnt and FGF) from the neighbouring tissues: the neural plate, the non-neural ectoderm and the paraxial mesoderm activate the NB specifiers [11]. Subsequently, the synergism between various NB specifiers in the presence of above mentioned inductive signals leads to the activation of another set of transcription factors known as NC specifiers [9]. Based on numerous studies in vertebrate animal models such as chick, Xenopus and lamprey, NC specifiers can be broadly classified into early and late groups [6,8,9].
During late gastrulation/early neurulation, the early NC specifiers such as snai2, foxd3, sox8 and sox9 induce and specify the premigratory NC cells in the dorsal neural tube [8,9]. In the second half of the neuration, the earlier NC specifiers lead to the induction of late NC specifiers (e.g., sox10, ets1, and twist1), which initiate the epithelial-mesenchymal transition (EMT) program in the premigratory NC cells. Following EMT, the NC cells migrate towards their destined locations in the embryo and differentiate into multiple derivatives [9,11,12].
==Neural crest and Sox E proteins==
Sox E proteins are neural crest specifiers downstream of and induced by neural plate border specifiers in vertebrates. In Xenopus laevis, Sox9 is expressed shortly after gastrulation at the lateral edges of the neural plate, in the NC-forming region (from stage 11 onwards). As development proceeds, Sox9 expression persists in migrating cranial crest cells as they populate the pharyngeal arches. Depletion of Sox9 protein in developing embryos, using morpholino antisense oligos, causes a dramatic loss of neural crest progenitors and an expansion of the neural plate [15]. Later during embryogenesis, morpholino-treated embryos have a specific loss or reduction of neural crest-derived skeletal elements, mimicking one aspect of the craniofacial defects observed in Campomelic Dysplasia patients. Sox9 is an essential component of the regulatory pathway that leads to cranial neural crest and cranial placode formation but, very little is known about its gene regulation mechanism. In Xenopus laevis, Sox10 expression accumulates from stage 13/14 onwards (early neurulation). It is expressed in prospective neural crest and otic placode regions from the earliest stages of NC specification and in migrating cranial and trunk neural crest cells. Loss-of-function experiments in Xenopus  using morpholino antisense oligos against SOX10 produce a loss of neural crest precursors and an enlargement of the surrounding neural plate and epidermis [16]. This effect of Sox10 depletion is produced during some of the earliest steps of NC specification, as is shown by the inhibition in the expression of Slug and FoxD3, which are early markers of neural crest specification. In addition, it has been shown that SOX10 depletion leads to an increase in apoptosis and a decrease in cell proliferation in the neural folds, suggesting that SOX10 could work as survival as well as a specification factor in NC precursors during pre-migratory stages. Mutations in one Sox10 allele have been found in patients that suffer from congenital aganglionic megacolon  (Hirschsprung disease), sometimes associated with a combination of pigmentation defects and deafness (Waardenburg–Shah syndrome).  The phenotype associated with this pathology indicates an important role for Sox10 in neural crest and otic placode development [17, 18].
==Cranial Placode Specification==
The ectodermal placodes were first described around the same time, depicted as ectodermal thickenings (Van Kuppfer, 1891). Thereafter, lineage tracing studies revealed that the placodes can give rise to multiple tissues, including both neurogenic and non-neurogenic. The cranial placodes are preceded by the formation of a preplacodal ectoderm, which is denoted by the expression of Six (1,2 4 and 5) and Eya (1 and 2), two important transcription factors. The preplacodal ectoderm forms in the anterior zone of the neural border which has low Wnt and low BMP signaling. At the end of neurulation, preplacodal ectoderm cells also undertake migration to different areas of the head to form the different cranial placodes, which have slightly distinct genetic identities. However, unlike the neural crest, they do not undergo EMT and instead delaminate and move away. Moreover, these migrating cells are essential for neural crest migration as they define the prospective migration routes. Later, they form the different cranial placodes –non-neurogenic adenohypophysis and lens, and neurogenic epibranchial, otic, paratympanic, trigeminal and olfactory. Aquatic anamniote vertebrates also possess the lateral line placodes, which forms mechanosensory organs in the head and the trunk. The placode cells also interact with the neural crest cells to form the cranial sensory ganglia.


==References==
==References==


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Suggested reading:
Hong C-S, Saint-Jeannet J-P. 2007. The Activity of Pax3 and Zic1 Regulates Three Distinct Cell Fates at the Neural Plate Border. MBoC 18:2192–2202. doi:10.1091/mbc.e06-11-1047


Neural crest history - Etchevers HC, Dupin E, Le Douarin NM. The diverse neural crest: from embryology to human pathology. Development, 146(5):dev169821 (2019).
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Cranial placodes – Schlosser G. Early embryonic specification of vertebrate cranial placodes. Wiley Interdiscip Rev Dev Biol. 2014;3(5):349-363. doi:10.1002/wdev.142
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Spokony RF, Aoki Y, Saint-Germain N, Magner-Fink E, Saint-Jeannet J-P. 2002. The transcription factor Sox9 is required for cranial neural crest development in Xenopus. Development 129:421–432.


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Figure 2
Vallin J, Thuret R, Giacomello E, Faraldo MM, Thiery JP, Broders F. 2001. Cloning and characterization of three Xenopus slug promoters reveal direct regulation by Lef/beta-catenin signaling. J Biol Chem 276:30350–30358. doi:10.1074/jbc.M103167200
Figure 1

Revision as of 11:46, 24 August 2023

Student Projects 2023: 1 Patterning neural border and NC | 2 NPB NEUcrest | 3 EMT and NC | 4 miRNA and NC | 5 Adrenal Gland and NC | 6 Melanocyte & Melanoma | 7 Neurocristopathies | Neural Crest
These projects are the sole work of undergraduate science students and may contain errors in fact or descriptions.

The patterning of the neural crest: its progenitor neural border domain and the pre-migratory neural crest cells. Neural crest (NC) development starts in the ectodermal germ layer during early embryogenesis, more precisely during gastrulation, simultaneously with the events of neural induction. It continues throughout neurulation and organogenesis (Eames et al., 2020). Here we focus on the first steps of NC formation. The induction of the NC fate takes place in a specific region of the ectoderm known as the neural plate border or better, the neural border, as part of this area is devoid of neural plate markers (NB/NPB). In the plane of the ectoderm, the NB is located between the non-neural ectoderm (prospective epidermis, positioned more laterally), and the neural plate (prospective CNS, positioned more medially). The NB ectoderm also lies above the paraxial and intermediate mesoderm (Alkobtawi et al., 2021; Milet and Monsoro-Burq, 2012). In addition, the NB ectoderm gives rise not only to NC cells but also to the cranial placodes (future sense organs), parts of the dorsal neural tube, and of the non-neural ectoderm (Schlosser, 2008). Tissue interactions play an essential role during NB and NC induction. Thus, NB induction is regulated by coordinated activation of different signals secreted by the surrounding tissues: the non-neural ectoderm, the neural plate, and the underlying mesoderm. The three main signaling pathways mediating these tissue interactions and ensuring the proper development of NC cells are the canonical Wnt/β-catenin signaling (WNT), the Bone Morphogenetic Protein (BMP), and Fibroblast Growth Factor (FGF) pathways. Multiple studies have shown that the activation of each of them is necessary but not sufficient alone and that they synergize to ensure appropriate levels of signaling targeted to the NB (Garnett et al., 2012; Hong and Saint-Jeannet, 2007; Monsoro-Burq et al., 2005; Saint-Jeannet et al., 1997; Tribulo et al., 2003); reviewed in (Prasad et al., 2019; Sutton et al., 2021). Globally, during vertebrate gastrulation, graded BMP signaling specifies the mediolateral body axis while graded WNT and FGF signaling specify the anteroposterior axis of the neural plate, with no/low levels acting at the anteriormost part and higher levels for posterior trunk regions (reviewed in (Sutton et al., 2021). BMP signals are secreted by the nonneural ectoderm and the underlying lateral mesoderm to maintain the nonneural ectodermal fate and together with WNT signals repress the neural fate (Faure et al., 2002; García-Castro et al., 2002). In turn, the axial mesoderm and the medial part of the neural plate secrete diffusible BMP antagonists allowing the expression of neural genes thus creating a BMP signaling gradient (Plouhinec et al., 2013). Thereby, the current textbook model is that high BMP activity induces an epidermal fate, moderate BMP levels induce NB genes, whereas low BMP activity determines a neural fate and represses both NB and ectodermal fates (Brugger et al., 2004; Marchant et al., 1998; Schumacher et al., 2011; Suzuki et al., 1997). However, recent findings highlight the action of BMP signaling potentiators which act in the paraxial and intermediate mesoderm and in the NB ectoderm, ensuring a high level of BMP signaling rather than an intermediate one (Alkobtawi et al., 2021). At the same time, inductive WNT and FGF signals are involved in the formation of the NB. FGF ligands are secreted by the mesoderm, the sources of WNT ligands could vary according to the species, and include ectoderm and mesoderm (García-Castro et al., 2002; Monsoro-Burq et al., 2003). In addition, there are also several auxiliary signaling participating in NB induction, e.g. retinoic acid and hedgehog signaling (Tribulo et al., 2003), but these have not yet been fully integrated into the gene regulatory network governing NB induction. The combination of WNT, BMP, and FGF pathways activates a complex network of transcription factors (TFs) within the neural border ectoderm, essential for NB induction and called the "NB specifiers". The most studied NB specifiers are Tfap2a, Gbx2, Msx1/2, Zic1, Pax3/7, and Hes4 (de Crozé et al., 2011; Monsoro-Burq et al., 2005; Sato et al., 2005; Simões-Costa and Bronner, 2015a). Once activated, the NB specifiers, along with extracellular signaling inputs (sustained or reactivated WNT signals for example), trigger the expression of downstream "NC specifiers": the transcription factors that are essential for NC induction and its further development: TFAP2B, SNAI1/2, FOXD3, TWIST1, SoxE genes (SOX8/9/10). In addition, some NB specifiers such as TFAP2A also act reiteratively as NC specifiers, regardless of their previous role (de Crozé et al., 2011; Simões-Costa and Bronner, 2015b). NC specifiers regulate NC induction of neural crest and further delamination of neural crest cells from neural tube via EMT but also activate downstream lineage-specific gene regulatory networks for the differentiation into distinct cell types. EMT is a process that is essential for the proper development of the neural crest and for the formation of many different tissue types. During EMT, cells undergo a series of changes that allow them to become more motile and migrate to different locations in the developing embryo. These changes include the loss of cell-cell adhesion, the acquisition of a more spindle-like shape, and the upregulation of various mesenchymal markers. There are several transcription factors that are known to play a critical role in the preparation of the neural crest for EMT. These include Snai1 and Snai2, transcriptional repressors, that have been extensively studied in the context of neural crest specification and EMT. Overexpression of Snail1/2 has been shown to increase the size of the neural crest population, while their inhibition blocks neural crest specification and migration. The regulatory regions of Snail2 contain binding sites for LEF/TCF and Smad1, which are directly regulated by WNT and BMP signaling (Nieto, 2018; Vallin et al., 2001). In addition, Snail1 and Snail2 are direct targets of Zic1 and Pax3 during frog neurulation.o defects in the development of the craniofacial skeleton and pigmentation (Plouhinec et al., 2014). Other transcription factors that have been implicated in the preparation of the neural crest for EMT include Twist1, which plays a role in the acquisition of a more spindle-like shape of the cells (Sepporta et al., 2022, p. 1). Twist1 directly interacts with the Snail1 and Snail2 proteins through its WR domain, and phosphorylation of Twist1 leads to the inhibition of the activity of Snail1 and Snail2 (Lander et al., 2013). Also, recent single-cell RNA sequencing data in mice and experimental manipulation of Twist1 expression in chick have demonstrated that Twist1 plays a role in regulating and promoting the mesenchymal fate choice (Soldatov et al., 2019). Another essential for the specification and maintenance of the NC genes is the SOXE family of transcription factors, including Sox8/9/10. However, each factor has distinct functions within the NC gene regulatory network. In frog development, Sox8 and sox9 are among the first NC specifier genes to be expressed in the neural plate region, prior to the expression of Snai2 and Foxd3 (Hong and Saint-Jeannet, 2007; Spokony et al., 2002). Sox10, on the other hand, is expressed later in pre-migratory NC cells. Both So9 and Sox10 are activated by the canonical WNT signaling pathway, and the expression of Sox10 is controlled by Sox9 and Snai2 (Spokony et al., 2002).


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