Abstract
The link between extrinsic signaling, progenitor cell specification and neuronal subtype identity is central to the developmental organization of the vertebrate central nervous system. In the hindbrain and spinal cord, distinctions in the rostrocaudal identity of progenitor cells are associated with the generation of different motor neuron subtypes. Two fundamental classes of motor neurons, those with dorsal (dMN) and ventral (vMN) exit points, are generated over largely non-overlapping rostrocaudal domains of the caudal neural tube. Cdx and Hox genes are important determinants of the rostrocaudal identity of neural progenitor cells, but the link between early patterning signals, neural Cdx and Hox gene expression, and the generation of dMN and vMN subtypes, is unclear. Using an in vitro assay of neural differentiation, we provide evidence that an early Wnt-based program is required to interact with a later retinoic acid- and fibroblast growth factor–mediated mechanism to generate a pattern of Cdx and Hox profiles characteristic of hindbrain and spinal cord progenitor cells that prefigure the generation of vMNs and dMNs.
Highlights
During the early development of the vertebrate central nervous system, the position of generation of post-mitotic neurons depends on the patterning of progenitor cells along the dorsoventral and rostrocaudal axes of the neural tube [1,2,3]
Cells in rhombomeres (r)3 and r5—here defined as the rostral hindbrain—express Krox20 (Figure1D, [33]) and generate both dorsal exiting motor neuron (dMN) defined by the expression of Tbx20þ/ Islþ and ventral exiting motor neuron (vMN) defined by the expression of Hb9þ/Islþ (Figure 1D, [34,35,36])
We examined whether prospective rostral hindbrain (rHB) and caudal spinal cord (cSC) cells have acquired sufficient rostrocaudal positional information by stage 4 to permit them to differentiate into dMNs or vMNs when exposed to Sonic hedgehog (Shh)-N
Summary
During the early development of the vertebrate central nervous system, the position of generation of post-mitotic neurons depends on the patterning of progenitor cells along the dorsoventral and rostrocaudal axes of the neural tube [1,2,3]. At an earlier developmental stage, neural progenitors have been shown to acquire caudal forebrain, midbrain, and rostral hindbrain positional identities in response to graded Wnt signaling at the gastrula stage [31,32] It is unclear, whether an early phase of Wnt signaling is required to establish Cdx and Hox gene expression profiles characteristic of the cHB and spinal cord, in turn specifying the generation of dMN and vMN subtypes. This study uses in vitro assays of neural cell differentiation to obtain evidence that early Wnt signaling does have a crucial role in specifying the identity of hindbrain and spinal cord progenitor cells as revealed by profiles of Cdx and Hox gene expression This early influence of Wnt signaling is later refined by retinoid and FGF signals to impart additional rostrocaudal distinctions in Hox expression that correlate tightly with the generation of dMNs and vMNs. Our findings define a crucial early role for Wnt signaling in inducing profiles of Cdx and Hox expression that prefigure the differentiation of dMN and vMN subtypes in the developing hindbrain and spinal cord
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