Key-notes on Neural Induction

Site: Cell Molecular Biology
Course: Developmental Neurobiology (Neuro)
Book: Key-notes on Neural Induction
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Date: Monday, 23 December 2024, 4:37 AM

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key notes

1. Neural Induction

All the cells of the vertebrate central nervous system derive from the neural plate, a region of columnar epithelium induced from the dorsal ectoderm during gastrulation.

Specification of the ectoderm    
The ectoderm is the outermost germ layer, which covers most of the metazoan embryo after gastrulation and give rise to epidermis, neural tissue and (in vertebrate embryos) the neural crest. 
In amphibians, the germ layers are specified early by distribution of maternal determinants in the developing oocyte. Factors involved in the specification of both mesoderm and endoderm have been identified, while no specific factors inducing ectodermal fate are known. Although a number of molecules influencing early ectoderm development have been isolated, they all appear to control the choice between epidermal and neural fates once the ectoderm is already specified. Thus, the ectoderm may represent a "default state" where cells do not receive signals that lead to mesodermal or endodermal specification. Transplantation experiments in which animal cap cells (presumptive ectoderm) were grafted to the vegetal hemisphere of an early blastula resulted in endodermal or mesodermal tissue. Conversely, the same experiments performed explanting from a late blastula stage embryo resulted in ectodermal tissue. Thus, although the ectoderm may be specified very early in development, its fate is not determined until the late blastula stage.
In amniotes,fate-mapping shows that presumptive ectoderm is represented by the epiblast anterior to the node and by lateral epiblast. Specification and determination of the ectoderm (as for the other germ layers) occurs later compared to amphibians, starting at gastrulation.The difference in timing between amphibians and amniotes germ layer specification probably relies in the fact that while early development in amphibians is strictly dependent on maternal factors differentially distributed in the egg, in amniotes, zygotic gene transcrition begins during early cleavage and there is extensive cell proliferation in the epiblast layer prior to and during gastrulation, allowing greater plasticity in patterning. 
 
Fate of the ectoderm
Three major components derive from the ectoderm:
1) the neural plate (gives rise to the CNS)
2) the epidermis 
3) the neural plate border (in between 1 and 2) - at the most anterior level gives rise to the ectodermal placodes (sensory organ development) - from the midbrain down, forms the neural crest (PNS+different cell types)
 
 
What is neural induction? 
is the process by which the ectoderm on the dorsal surface of the vertebrate embryo forms the neural plate. The neural plate later folds to form the neural tube through a process called neurulation (Read chapter "Formation of the neural tube") and eventually develops into the brain and spinal cord. 
The ectoderm is induced to form the neural plate during gastrulation under the influence of dorsalizing signals secreted by the underlying dorsal mesoderm of the organizer (the organizer is said to dorsalize or neuralize the overlying ectoderm). The neurogenic ectoderm begins to express neural cell markers (e.g. Sox2 and Sox3), and differentiates to form tall columnar cells. The ability of dorsal mesoderm of the organizer to induce overlying ectoderm to form neural plate has been discovered following the "organizer graft experiments" by Spemann and Mangold in 1924. (Watch the video on Spemann's experiments). The research on the molecular interactions underlying neural induction in different vertebrates is still ongoing.

1.1. The neural default model

This model (nowadays considered too simplistic)  is based on data obtained from experimental studies mostly performed in Xenopus. When animal cap tissue (tissue situated around the animal-pigmented- pole of a very early gastrula-stage embryo) is explanted and cultured in isolation in vitro it differentiates into epidermis. However, if the animals cap tissue is dissociated in culture, the individual cells differentiate into neurons. This suggested that the default developmental pathway is neural and that epidermal fate arises from a community effect in which molecules produced by the ectoderm itself suppress neural development. Instead, isolated cells do not produce sufficient amounts of these molecules to prevent neural differentiation and thus single cells spontaneously develop into neurons. The role of the organizer is to inhibit these molecules allowing the latent neural potential of the ectoderm to develop. 
Several experimental evidences indicate that the key molecular players in the inhibition of neural differentiation of the ectoderm are members of the bone morphogenetic protein (BMP- i.e BMP2, BMP4 and BMP7) family of the TGFbeta superfamily). For example, interfering with BMP signalling pathway by expressing dominant negative BMPs or BMPs receptors, or antisense bmp RNA, results in a dorsalized embryo with all ectodermal cells becoming neural. BMPs play a fundamental role in specifying ventral cell fates in the Xenopus embryo. The effect of BMP signaling is opposed by dorsalizing signals from the organizer. Among anti-BMP proteins with neural inducing activity are: Noggin, Chordin, Follistatin and Cerberus that exert their activity by binding directly to several BMPs with greater affinity compared to the corresponding BMP receptors (competitive inhibition of BMP activity).
 
 
 
default
Other molecules secreted by the organizer (e.g Xenopus nodal related 3 - Xnr3) exert their inhibitory effect by competing for BMP receptors or shared intracellular signal transduction proteins (SMADs). The competitive inhibition of BMPs by proteins secreted by the organizer results in a gradient of BMP activity from ventral to dorsal in the embryo: in the dorsal ectoderm, where there is low BMP activity, the neural plate is induced.

1.2. Genetic redundancy

The BMP patterning system that underlies neural induction in vertebrates is notable for extensive redundancy in gene function that has made a loss-of-function approach problematic: mutations that eliminate only one of these inhibitors tend to have relatively mild phenotypes on their own. For example, a loss-of-function mutation in Zebrafish chordin (the chordino mutant) causes only a reduction in the size of the neural plate while mouse embryos that lack just one the BMP antagonists, chordin or noggin, by knockout mutations have a relatively normal nervous system. However, the full potential of these antagonists became apparent when several of them are removed at the same time. A complete loss of neural tissue is observed when all three BMP antagonists, chordin, follistatin and noggin, are simultaneously targeted using morpholinos, both in Xenopus and in Zebrafish.

1.3. FGF signaling in neural induction

The default model is based on the idea that inhibiting BMP signaling is both necessary and sufficient to induce neural tissue to form, and that the organizer secretes BMP inhibitors to assure that BMP signaling is kept low on the dorsal side where neural tissue form. Thus, differential BMP signaling in Xenopus and zebrafish fulfills the expectation of an instructive mechanism for determining why neural tissue forms in one place in the embryo but not another. The default model, however, leaves open the possibility that other factors are involved in neural induction, including those operating in a more permissive fashion to alter the competence of the ectoderm. This is critical in birds and mammals where the spatial and temporal expression pattern of the BMPs and their inhibitors does not fit with the neural default model of induction. The best evidence for a factor is for fibroblast growth factor (FGF) and IGF, a ligand that binds to its receptors and signals via the MAPK cascade. FGF signaling is prominent in the early embryos during the process of mesodermal induction, and has also been shown to play an important role in posterior neural patterning. Significantly, FGF signaling has also been shown to inhibit BMP signaling in the early embryo by several mechanisms, thus potentially influencing the response of tissue to the activity of the BMP inhibitors produced by the organizer during neural induction. FGF signaling can promote phosphorylation of the linker domain and degradation of Smad1, thus reducing the efficacy of BMP signaling. FGF signaling can also inhibit BMP activity indirectly, by inducing the expression of a protein called SIP1, a zinc-finger, homeodomain protein, that binds to and represses the transcriptional activity of the Smad protein. For much of the neural plate, the role of FGF signaling is likely to be minor, since neural induction by the BMP inhibitors occurs readily in Xenopus in the absence of FGF signaling. Nonetheless, for the parts of the posterior neural plate located far from the organizer on the blastula fate map, prior FGF signaling may be required as a priming mechanism to suppress BMP signaling, so that the BMP antagonists can consolidate and maintain a commitment to a neural fate at later stages.

Read the book chapter "FGF signaling in neural induction"