Nervous System Regionalization Entails Axial Allocation before Neural Differentiation

Abstract

SummaryNeural induction in vertebrates generates a CNS that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity; caudalizing signals then convert a proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility to define how cells adopt region-specific neural fates. Together with genetic and biochemical perturbations, this identified a developmental time window in which genome-wide chromatin-remodeling events preconfigure epiblast cells for neural induction. Contrary to the established model, this revealed that cells commit to a regional identity before acquiring neural identity. This “primary regionalization” allocates cells to anterior or posterior regions of the nervous system, explaining how cranial and spinal neurons are generated at appropriate axial positions. These findings prompt a revision to models of neural induction and support the proposed dual evolutionary origin of the vertebrate CNS.

New roles for Wnt and BMP signaling in neural anteroposterior patterning

“…FGF induction of cdx gene expression activates spinal cord hox gene expression, while simultaneously repressing more anterior hindbrain hox gene expression [48,[69][70][71][72]. A recent study in chick and mouse embryos suggests that regionalization of the spinal cord and activation of cdx gene expression is separated in time and space from the induction of the hindbrain/forebrain regions [73]. This study emphasizes that different lineage origins separate these different neural AP regions.…”

“…In Xenopus, we suggest that the caudalizing forces driving neural AP pattern are the "earlier" Wnt-Meis3-FGF activity that induces the hindbrain [24,25,37], which is coupled to a "later" BMP-FGF-Cdx activity that specifies the spinal cord [48,71,72,74]. This separation of time, space, and signaling for the hindbrain and spinal cord [31,73] does not fit a model in which a single gradient of Wnt signaling demarcates the entire AP character of the nervous system.…”

A critical look: Challenges in differentiating human pluripotent stem cells into desired cell types and organoids

“…The neural ectoderm was previously construed to constitute a uniform precursor population that underwent anterior-posterior patterning to form the forebrain, midbrain, hindbrain and spinal cord (reviewed by Lumsden & Krumlauf, 1996). However, a new emerging hypothesis is that the brain and spinal cord have distinct developmental origins and that they do not originate from a single, monolithic "neural ectoderm" precursor (Henrique, Abranches, Verrier, & Storey, 2015;Metzis et al, 2018). It has been hypothesized that neural ectoderm forms the brain, whereas a distinct "neuromesoderm" progenitor (variously referred to as "caudal lateral epiblast" or "axial progenitors") conceives the spinal cord in addition to the presomitic mesoderm (Takemoto et al, 2011;Tzouanacou, Wegener, Wymeersch, Wilson, & Nicolas, 2009) (Figure 2di).…”

Transformation of a neural activation and patterning model

“…Nevertheless, it remained formally possible that newly generated spinal cord cells coming from the NMPs first passed through an anterior forebrain intermediate before becoming spinal cord. This notion was conclusively laid to rest by a recent study from Metzis et al, which showed cells first adopt an axial position and then undergo neural fate acquisition appropriate to that axial level, and in so doing spinal cord cells do not pass through an anterior neural (brain) intermediate state [8].…”