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FGF expression in the vertebrate nervous system The isolation of zebrafish Fgf8 and its expression during gastrulation, somitogenesis, fin
bud and early brain development is described. By demonstrating genetic linkage and by analysing the structure of the Fgf8 gene, it is shown that acerebellar is a zebrafish Fgf8 mutation that may inactivate Fgf8 function. Homozygous acerebellar embryos lack a cerebellum and the midbrain-hindbrain boundary organizer. Fgf8 function is required to maintain, but not initiate, expression of Pax2.1 and other marker genes in this area. Fgf8 and Pax2.1 are activated in adjacent domains that only later become overlapping; activation of Fgf8 occurs normally in no isthmus embryos that are mutant for Pax2.1. These findings suggest that multiple signaling pathways are independently activated in the midbrain-hindbrain boundary primordium during gastrulation, and that Fgf8 functions later during somitogenesis to polarize the midbrain. Fgf8 is also expressed in a dorsoventral gradient during gastrulation and ectopically expressed Fgf8 can dorsalize embryos. Nevertheless, acerebellar mutants show only mild dorsoventral patterning defects. Also, in spite of the prominent role suggested for Fgf8 in limb development, the pectoral fins are largely unaffected in the mutants. Fgf8 is therefore required in development of several important signaling centers in the zebrafish embryo, but may be redundant or dispensable for others (Reifers, 1998).
Gain-of-function assays in Xenopus have demonstrated that Xwnt-3a can pattern neural
tissue by reducing the expression of anterior neural genes, and elevating the expression of posterior
neural genes. To date, no loss-of-function studies have been conducted in Xenopus to show a
requirement of endogenous Wnt signaling for patterning of the neural ectoderm along the
anteroposterior axis. Expression of a dominant negative Wnt in Xenopus embryos
causes a reduction in the expression of posterior neural genes, and an elevation in the expression of
anterior neural genes, thereby confirming the involvement of endogenous Wnt signaling in patterning
the neural axis. The ability of Xwnt-3a to decrease expression of anterior
neural genes in noggin-treated explants (noggin is a neural inducer) is dependent on a functional FGF signaling pathway, while
the elevation of expression of posterior neural genes does not require FGF signaling. In Xenopus, eGFG, FGF3 and XFGF-9 are expressed in the posterior dorsal mesoderm during gastrulation, consistent with potential roles in neural patterning. The previously
reported ability of FGF to elevate the expression of posterior neural genes in noggin-treated explants
is found to be dependent on endogenous Wnt signaling. It is concluded that neural induction occurs
initially in a Wnt-independent manner, but that generation of complete anteroposterior neural pattern
requires the cooperative actions of Wnt and FGF pathways. Noggin induces the anterior markers Xanf-1 and Otx-2 in animal cap explants but in the presence of Xwnt-3a, expression of both markers is reduced. At the same time there is an elevation in expression of the posterior neural markers En-2 and Krox-2, although not the spinal cord marker Hox B9. In the presence of FGF, noggin (in contrast) does not reduce the expression of Xanf-1 or Otx-2, while there is a concurrent induction of posterior genes, including Hox B9. Thus Wnts and FGF can both pattern neural tissues but these factors exhibit differences in their neural patterning activities. Xwnt-3a cannot suppress anterior neural genes in the absence of FGF signaling, indicating that the two pathways work together in neural patterning (McGrew, 1997).
Fibroblast growth factor 2 (FGF2) and FGF receptors are transiently expressed by cells of the pseudostratified ventricular epithelium (PVE) during early neurogenesis. A single microinjection of FGF2 into cerebral ventricles of rat embryos at E15.5 increases the volume and total number of neurons in the adult cerebral cortex by 18% and 87%, respectively. Microinjection of FGF2 by the end of neurogenesis, at E20.5, selectively increases the number of glia. Mice lacking the FGF2 gene have fewer cortical neurons and glia at maturity. BrdU studies in FGF2-microinjected and FGF2-null animals suggest that FGF2 increases the proportion of dividing cells in the PVE without affecting the cell-cycle length. Thus, FGF2 increases the number of rounds of division of cortical progenitors (Vaccarino, 1999).
The developing vertebrate mesencephalon shows a rostrocaudal gradient in
the expression of a number of molecular markers and in the cytoarchitectonic
differentiation of the tectum, where cells cease proliferating and differentiate
in a rostral to caudal progression. Tissue grafting experiments have
implicated cell signaling by the mesencephalic-metencephalic
(mid-hindbrain) junction (or isthmus) in orchestrating these events. The role of Wnt-1 (Drosophila homolog: Wingless) and FGF8 signaling has been explored in the regulation of
mesencephalic polarity. FGF8 is expressed in cardiac mesoderm underlying the presumptive mesencephalic/metencephalic region and may play a role in mesencephalic induction. Fgf8 is also expressed in the neural plate itself, in the most rostral metencephalon. Wnt-1 is expressed in the caudal mesencephalon. Wnt-1 regulates Fgf8 expression in
the adjacent metencephalon, most likely via a secondary mesencephalic
signal. Ectopic expression of Fgf8 in the mesencephalon is sufficient to
activate expression of Engrailed-2 (Drosophila homolog: Engrailed) and ELF-1, two genes normally
expressed in a decreasing caudal to rostral gradient in the posterior
mesencephalon. ELF-1 is a ligand for a EPH-like receptor tyrosine kinase expressed in rostrocaudally increasing gradients across the caudal tectum and may function to inhibit temporal axon ingrowth and/or to attract nasal axons. Ectopic expression of Engrailed-1, a functionally
equivalent homolog of En-2 is sufficient to activate ELF-1 expression by
itself. These results indicate the existence of a molecular hierarchy in which
FGF8 signaling establishes the graded expression of En-2 within the tectum.
This in turn may act to specify other aspects of A-P polarity such as graded
ELF-1 expression. FGF8 is a potent mitogen
within the mesencephalon: when ectopically expressed, neural precursors
continue to proliferate and neurogenesis is prevented. Taken together these
results suggest that FGF8 signalling from the isthmus has a key role in
coordinately regulating growth and polarity in the developing mesencephalon. It is unlikely that the normal sourse of FGF8 is the brain, as expression is not initiated in the mes/met region until 3-somites. This is after the regional activation of several genes in the presumptive mes/met region, including Pax-2, Wnt-1 and En-1. The issue of whether FGF8 plays a direct role in mesencephalon induction from cardiogenic mesodermal cells remains an open question. Engrailed itself may play an earlier role in mesencephalic specification. It is clear at least that FGF8 signaling plays an important role in the regulation of growth and polarity in the mesencephalon (Lee, 1997).
Rat FGF-9 mRNA is moderately or weakly expressed in widespread regions
including the olfactory bulb, caudate putamen, cerebral cortex, hippocampus, thalamus,
hypothalamus, midbrain, brainstem and cerebellum. However, FGF-9 mRNA is also strongly
expressed in several specific nuclei including the red nucleus and oculomotor nucleus in the
midbrain, the vestibular nucleus and facial nucleus in the brainstem, and the medial cerebellar
nucleus, interposed cerebellar nucleus and lateral cerebellar nucleus in the cerebellum. The cellular
localization of FGF-9 mRNA indicates that the mRNA in the rat brain is expressed
preferentially in neurons, although FGF-9 was originally isolated from human glioma cells. The
localization profile of FGF-9 mRNA is different from those of aFGF, bFGF and FGF-5 mRNAs (Tagashira, 1995).
Acidic and basic fibroblast growth factors (aFGF and bFGF, respectively) are expressed in high
levels in adult rat central nervous system (CNS). Sensory neurons in the midbrain are the first cells to contain detectable aFGF
immunoreactivity at embryonic day 18. The next cell group to contain aFGF were motor neurons,
which are found to be aFGF-positive at the day of birth. A number of other subcortical neuronal
populations are observed to contain aFGF immunoreactivity after postnatal day 7. Adult levels
and distribution patterns of aFGF are reached in all CNS areas by postnatal day 28. Basic FGF
immunoreactivity is observed at postnatal day 0 in neurons in the CA2 subfield of hippocampus.
Astrocytes contain detectable bFGF immunoreactivity, starting at postnatal day 7. Adult levels
and patterns of distribution of bFGF are reached in all CNS areas by postnatal day 28.
FGFR-1 and FGFR-2 mRNA are expressed in significant levels in all CNS areas. The observation that aFGF and bFGF appear in specific and distinct cellular
populations at relatively late developmental times suggests that these FGFs may be involved in
specific mechanisms of CNS maturation, maintenance, and repair (Kuzis, 1995).
Basic fibroblast growth factor (bFGF) plays an important role in development of the central nervous system
and is neurotropic for a variety of neurons. bFGF is neurotropic for
GT1 GnRH neuronal cells that express functional FGF receptors (FGFRs). The GT1 cell lines
generated by genetically targeted tumorigenesis display highly differentiated properties of GnRH neurons.
Addition of bFGF increases neurite outgrowth of GT1 cells and results in a significant
increase of GT1 cell survival in serum-free medium. GT1 cells express FGFRs 1 and 3 but not 2. Occupancy of FGFRs with bFGF stimulates the
sustained tyrosine phosphorylation of both the 42- and 44-kilodalton mitogen-activated protein kinases
(MAPKs). GT1 cells also express
messenger RNA for bFGF, although the level appears
suboptimal because GT1 cells can further respond to exogenously added bFGF. Thus, bFGF is a neurotropic factor in GT1 GnRh neuronal cell lines, raising the possibility that bFGF may play
a role in the neurobiology of GnRH neurons (Tsai, 1995).
During differentiation of the embryonic anterior pituitary,
distinct hormone cell types are generated in a precise temporal and spatial order from an apparently
homogenous ectodermal primordium. The anterior pituitary derives from Rathke's pouch (RP), a specialized region of the oral roof ectoderm. The posterior pituitary derives from the infundibulum (INF) an evagination of the ventral diencephalon. Evidence is provided that in RP, the coordinate control of
progenitor cell identity, proliferation and differentiation is imposed by spatial and temporal restrictions in
FGF- and BMP-mediated signals. These signals derive from adjacent neural and mesenchymal
signaling centers: the infundibulum and ventral juxtapituitary mesenchyme (VJM), respectively. The infundibulum appears to
have a dual signaling function, serving initially as a source of BMP4 and subsequently of FGF8. The onset of FGF8 expression in the INF coincides with that of Lhx3 expression in RP. The ability of the INF over the period E10.5 to E12.5 to extinguish Isl1 (in the dorsal aspect of the RP) and promote Lhx3 in the same region corresponds more closely to the temporal expression of FGF8 than of BMP4. FGF8 can mimic the ability of the INF to repress Isl1 and maintain Lhx3 expression in explants. In vitro, FGFs promote the proliferation of progenitor cells, prevent their exit from the cell cycle and contribute to the specification of progenitor cell identity. Late FGF8 signaling controls corticotroph differentiation in the dorsal Lhx3+, Isl1- domain. Maintained FGF8 signaling from the INF expands still further the dorsal corticotroph prrogenitor population; as a consequence, the most ventral of these progenitors become located beyond range of FGF signaling. Since these progenitors are also beyond range of, or by this time refractory to, BMP2/7 signals (derived from the VJM), they progress to an ACTH+ definitive corticotroph state (Ericson, 1998).
The ventral domain of RP serves as the origin of thyrotrophs, defined by expression of the alpha-glycoprotein and thyroid stimulating hormone beta subunits. The continued proliferation of progenitor cells in the dorsal domain of RP (stimulated by FGF8 signals derived from the INF) results in the progressive ventral displacement of thyrotroph progenitors such that they come to be located beyond the range of FGF8 signaling. The
ventral juxtapituitary mesenchyme appears to serve as a later source of BMP2 and BMP7. BMPs have no apparent effect on cell
proliferation but instead appear to act with FGFs to control the initial selection of thyrotroph and
corticotroph progenitor identity. BMPs promote prospective thyrotroph differentiation and suppress corticotroph differentiation. BMPs expressed by the VJM promote Isl1 expression in the ventral domain of RP. Ultimately cells in the ventral domain begin to express TSHbeta and alpha-glycoprotein, having become established as definitive thyrotrophs (Ericson, 1998).
Four new members of the fibroblast growth factor (FGF) family, referred to as fibroblast growth factor
homologous factors (FHFs), have been identified by a combination of random cDNA sequencing, data
base searches, and degenerate PCR. Pairwise comparisons between the four FHFs show between
58% and 71% amino acid sequence identity, but each FHF shows less than 30% identity when
compared with other FGFs. Like FGF-1 (acidic FGF) and FGF-2 (basic FGF), the FHFs lack a
classical signal sequence and contain clusters of basic residues that can act as nuclear localization
signals. In transiently transfected 293 cells, FHF-1 accumulates in the nucleus and is not secreted. Each
FHF is expressed in the developing and adult nervous systems, suggesting a role for this branch of the
FGF family in nervous system development and function (Smallwood, 1996).
The anterior neural ridge (ANR), and the isthmic organizer (IsO) represent two signaling centers possessing organizing properties necessary for forebrain (ANR) as well as midbrain and rostral hindbrain (IsO) development. An important mediator of ANR and IsO organizing property is the signaling molecule FGF8. Previous work has indicated that correct positioning of the IsO and Fgf8 expression in this domain is controlled by the transcription factors Otx2 and Gbx2. In order to provide novel insights into the roles of Otx2 and Gbx2, mutant embryos carrying different dosages of Otx2, Otx1 and Gbx2 were studied. Embryos deficient for both OTX2 and GBX2 proteins (hOtx12/hOtx12; Gbx2-/-) show abnormal patterning of the anterior neural tissue, that is evident at the presomite-early somite stage prior to the onset of Fgf8 neuroectodermal expression. Indeed, hOtx12/hOtx12; Gbx2-/- embryos exhibit broad co-expression of early forebrain, midbrain and rostral hindbrain markers such as hOtx1, Gbx2, Pax2, En1 and Wnt1 and subsequently fail to activate forebrain and midbrain-specific gene expression. In this genetic context, Fgf8 is expressed throughout the entire anterior neural plate, thus indicating that its activation is independent of both OTX2 and GBX2 function. Analysis of hOtx12/hOtx12; Gbx2-/- and Otx1+/-; Otx2+/- mutant embryos also suggests that FGF8 cannot repress Otx2 without the participation of GBX2. Embryos carrying a single strong hypomorphic Otx2 allele (Otx2lambda) in an Otx2 and Gbx2 null background (Otx2lambda/-; Gbx2-/-) recover both the headless phenotype exhibited by Otx2lambda/- embryos and forebrain- and midbrain-specific gene expression that is not observed in hOtx12/hOtx12; Gbx2-/- mutants. Together, these data provide novel genetic evidence indicating that OTX2 and GBX2 are required for proper segregation of early regional identities anterior and posterior to the mid-hindbrain boundary (MHB) and for conferring competence to the anterior neuroectoderm in responding to forebrain-, midbrain- and rostral hindbrain-inducing activities (Martinez-Barbera, 2001).
Regeneration of the spinal cord occurs spontaneously in adult urodele amphibians. The key cells in this regenerative process
appear to be the ependymal cells that, following injury, migrate and proliferate to form the ependymal tube from which the
spinal cord regenerates. Very little is known about the signal(s) that initiates and maintains the proliferative response of
these cells. Fibroblast growth factor 2 (FGF-2) has been shown to play a role in maintaining neural progenitor cell cycling
in vitro and may be important for neuronal survival and axonal growth after injury. Its role in
regeneration of the spinal cord has been investigated in vivo following tail amputation in the adult salamander, Pleurodeles waltl. Only the low-molecular-weight form of FGF-2 is found in Pleurodeles and in the normal cord it is expressed in a subset
of neurons, but is hardly detectable in ependymal cells. Tail amputation results in induction of FGF-2 in the ependymal cells
of the regenerating structure, and later in regeneration FGF-2 is up-regulated in some newborn neurons. The FGF-2 pattern of
expression in the ependymal tube parallels that of proliferation. Furthermore, exogenous FGF-2 significantly increases
ependymal cell proliferation in vivo. Overall these results strongly support the view that one important role of FGF-2 during
spinal cord regeneration in Pleurodeles is to induce proliferation of neural progenitor cells (Zhang, 2000).
Subclasses of motor neurons are generated at different positions along the rostrocaudal axis of the spinal cord. One feature of the rostrocaudal organization of spinal motor neurons is a position-dependent expression of Hox genes, but little is known about how this aspect of motor neuron (MN) subtype identity is assigned. The expression profile of Hox-c proteins has been used to define the source and identity of patterning signals that impose motor neuron positional identity along the rostrocaudal axis of the spinal cord. Evidence has been provided that the convergent activities of FGFs, Gdf11, and retinoid signals originating from Hensen's node (HN) and paraxial mesoderm establish and refine the Hox-c positional identity of motor neurons in the developing spinal cord (Liu, 2001).
The profile of Hox-c inductive activity exhibited by HN coincides well with the expression pattern of FGF genes, notably Fgf8. FGFs act in vitro in a graded manner, with higher concentrations of FGFs inducing a progressively more caudal profile of neural Hox-c expression. Similarly, activation of FGF receptor signaling in vivo induces a rostral-to-caudal shift in the profile of Hox-c expression. Not all ectopic Hoxc9+ and Hoxc10+ cells located in the ventral spinal cord express MN markers, which may indicate additional actions of high level FGF signaling on MN differentiation. Nevertheless, together these in vitro and in vivo findings indicate that graded FGF signals derived from HN are likely to initiate the neural pattern of Hox-c expression. Such graded signaling could be achieved by a stage-dependent increase in the level of FGF signaling from HN since the level of Fgf8 expression in HN appears to increase in older embryos. Alternatively, since neural cells fated to give rise to progressively more caudal regions of the spinal cord are positioned close to HN for progressively longer periods, they may be exposed to the same level of FGF signaling as cells destined to populate more rostral regions of the spinal cord, but for a longer period. Recent studies have provided evidence that FGF signaling within HN promotes the proliferation of prospective neural cells, maintaining a progenitor cell population throughout the period of spinal cord elongation. Thus, FGF signaling within HN may coordinate the proliferation and R-C specification of spinal progenitor cells (Liu, 2001).
The onset of expression of the Hox-c proteins by spinal MNs occurs after neurons have left the cell cycle, yet patterned Hox-c expression is specified at the time of neural plate formation. How is the early specification of positional identity linked to the expression of Hox-c proteins in MNs? In Xenopus, the FGF-dependent regulation of Hox gene expression in mesodermal and neural cells involves Cdx genes. Different members of Cdx gene family appear to be expressed at different R-C levels during early stages of chick neural development. Thus, Cdx genes are plausible mediators of FGF signaling in the regulation of Hox-c expression within MNs (Liu, 2001).
Many aspects of the R-C pattern of Hox-c expression in spinal MNs can be accounted for by the action of FGFs provided by HN. But three observations indicate that additional signals are required to achieve the profile of Hox-c expression evident at cervical and lumbar levels. (1) Neither HN nor FGFs induce the neural expression of Hoxc5, a Hox-c protein that delineates cervical levels of the spinal cord. (2) Segments of the thoracic neural tube isolated after the influence of HN-derived signals exhibit ectopic caudal expression of Hoxc6, suggesting that the normal caudal limit of Hoxc6 expression is defined by signals that act later than those provided by HN. (3) Hoxc10 expression is induced only at very high FGF concentrations, suggesting that the acquisition of a caudal Hox-c profile requires additional signals (Liu, 2001).
One source of these additional signals appears to be the paraxial mesoderm. Paraxial mesodermal signals refine the R-C pattern of neuronal Hox-c expression initiated by FGF signals from the primitive streak and HN. Rostral paraxial mesoderm expresses high levels of retinoid signaling activity, and retinoids rather than FGFs induce the expression of Hoxc5 at cervical levels. Retinoid signaling also refines the expression pattern of Hox-c proteins whose expression is initiated by FGF signals from HN. Retinoid signaling from rostral paraxial mesoderm therefore appears necessary to establish a cervical profile of Hox-c expression in MNs. By the time of its caudal expression, the initial specification of neural Hox-c expression has been established, and there has been a marked decrease in the competence of thoracic neural tissue to respond to retinoid signaling with changes in Hox-c expression (unpublished observations). At these more caudal levels, HN and the paraxial mesoderm selectively expresses Gdf11, a member of the TGFß family. Gdf11 alone appears to have little Hox-c-inducing ability, but in conjunction with FGF signaling, markedly alters the profile of Hox-c expression. The prominent expression of Hoxc9 and Hoxc10 normally observed at caudal thoracic and rostral lumbar levels of the spinal cord may therefore be achieved through the joint exposure of neural cells to FGFs and Gdf11 (Liu, 2001).
Sonic hedgehog (Shh) is a key signal in the specification of ventral cell identities along the length of the developing vertebrate neural tube. In the presumptive hindbrain and spinal cord, dorsal development is largely Shh independent. By contrast, Shh is required for cyclin D1 expression and the subsequent growth of both ventral and dorsal regions of the diencephalon and midbrain in early somite-stage mouse embryos. It is proposed that a Shh-dependent signaling relay regulates proliferation
and survival of dorsal cell populations in the diencephalon and midbrain. Evidence is presented that Fgf15 shows Shh-dependent
expression in the diencephalon and may participate in this interaction, at least in part, by regulating the ability of dorsal neural
precursors to respond to dorsally secreted Wnt mitogens (Ishibashi, 2002).
While many neuronal differentiation genes have been identified, little is known about what determines when and where neurons will form and how this process is coordinated with the differentiation of neighboring tissues. In most vertebrates the onset of neuronal differentiation takes place in the spinal cord in a head to tail sequence. The changing signaling properties of the adjacent paraxial mesoderm control the progression of
neurogenesis in the chick spinal cord. An inverse relationship is found between the expression of caudal neural genes in the prospective spinal cord, which is maintained by underlying presomitic mesoderm and FGF signaling, and neuronal differentiation, which is repressed by such signals and accelerated by somitic mesoderm. Key to this interaction is the ability of somitic mesoderm to repress
Fgf8 transcription in the prospective spinal cord. These findings further indicate that attenuation of FGF signaling in the prospective spinal cord is a
prerequisite for the onset of neuronal differentiation and may also help to resolve mesodermal and neural cell fates. However, inhibition of FGF
signaling alone does not promote the formation of neurons, which requires still further somite signaling. A model is proposed in which signaling from
somitic tissue promotes the differentiation of the spinal cord and serves to co-ordinate neural and mesodermal development (Diez del Corral, 2002).
Two lines of evidence are presented that strongly suggest that signals from the differentiating somitic mesoderm regulate the onset of neuronal differentiation in the developing spinal cord: (1) somitic signals accelerate the appearance of neurons in caudal neural plate (CNP) explants, as indicated by the swift onset of Delta 1 in single cells, NeuroM expression and the appearance of cells with neurofilament-positive fine processes; and (2) these signals are also required in vivo for the normal onset of neuronal differentiation, as revealed by the strikingly few NeuroM-positive cells in neural tube forming in the absence of the differentiating somitic mesoderm. Removal of somites flanking the later neural tube also depletes the number of NeuroM-expressing cells, while Sox2 and Delta 1 expression remain unaltered, indicating that there is a continuing requirement for somite signals for neurogenesis progression. However, it is likely that somites become dispensable for the production of neurons at later stages, because their removal at stages 12-16 does not alter the number of motor neurons. This suggests that the influence of somite-derived factors is confined to the first born neurons (future reticular and spinal interneurons). Since explants of the neural tube readily form neurons in vitro, this requirement for somite signals in vivo suggests that these signals normally act to oppose other signals present in the neural tube that repress neuronal differentiation (Diez del Corral, 2002).
Evidence is also presented that somitic signals repress the caudal neural gene cash4, consistent with its down regulation in vivo prior to neuronal differentiation. Sax1 expression was not consistently altered by such signals. This apparent difference in regulation may reflect the later onset of Sax1 expression or its regulation by other signals in the embryo. Indeed, removal of the presomitic mesoderm in vivo leads to the loss of cash4 and Sax1, suggesting that during normal development repression of caudal neural genes is mediated by a combination of 1) signal loss, as the presomitic mesoderm differentiates, and 2) exposure to signals from the newly formed somites. In this context it is striking that removal of the presomitic mesoderm also leads to the precocious appearance of NeuroM-positive cells in the preneural tube in a small number of cases. This suggests that the presomitic mesoderm not only maintains caudal neural genes, but also represses neuronal differentiation. This in vivo situation contrasts with CNP explants cultured alone in vitro (for 24 hours), which maintain cash4 and Sax1 and do not contain neurons. This difference may be explained if mesoderm cells in CNP explants (which in vivo would have been displaced during gastrulation) provide signals that maintain caudal neural genes and repress NeuroM. In addition other tissues/signals may be present in the embryo, which normally oppose signals from the presomitic mesoderm and which act swiftly following removal of this tissue in vivo. These opposing signals could be provided by the notochord/floor plate at the ventral midline and/or by abutting NeuroM-positive spinal cord (which has been exposed to somites). Together, these findings indicate that the onset of neuronal differentiation in the spinal cord is regulated by a balance between signals provided by the presomitic mesoderm and the somites and that both these tissues may act in the embryo to counter opposing signals (Diez del Corral, 2002).
In the vertebrate embryo, spinal cord elongation requires FGF signaling that promotes the continuous development of the posterior nervous system by maintaining a stem zone of proliferating neural progenitors. Those escaping the caudal neural stem zone initiate ventral patterning in the neural groove before starting neuronal differentiation in the neural tube. The integration of D-type cyclins, known to govern cell cycle progression under the control of extracellular signals, in the program of spinal cord maturation was investigated. In chicken embryo, it was found that cyclin D2 is preferentially expressed in the posterior neural plate, whereas cyclin D1 appears in the neural groove. Loss- and gain-of-function experiments demonstrate that FGF signaling maintains cyclin D2 in the immature caudal neural epithelium, while Shh activates cyclin D1 in the neural groove. Moreover, forced maintenance of cyclin D1 or D2 in the neural tube favors proliferation at the expense of neuronal differentiation. These results contribute to the understanding of how the cell cycle control can be linked to the patterning programs to influence the balance between proliferation and neuronal differentiation in discrete progenitors domains (Labjois, 2004)
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Previous studies have implicated early retinoid signaling in establishing the generic character of the spinal cord, and later retinoid signaling in defining the pattern of Hox gene expression in the developing hindbrain (Liu, 2001).
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