Early Rostrocaudal Patterning of the CNS

Sammanfattning: The transformation of an initially uniform population of epiblast cells into an intricately complex central nervous system (CNS) is one of the most fascinating processes during embryonic development. Presumptive neural cells are initially specified as cells of forebrain character. Studies in various vertebrates have indicated that cells of more caudal neural character, that will generate the brain stem and spinal cord, are generated through the reprogramming of these initial rostral cells. The initial regionalization of these neural progenitor cells is central to all further diversification of neuronal cell types and the subsequent formation of functional euronal circuits. The aim of this thesis has been to enhance our understanding of which stages of embryonic development that are critical for the initial rostrocaudal regionalization of neural precursor cells, and which signaling mechanisms that orchestrate this early diversification.Both human and chick embryos have the shape of a flat disc during gastrulation. At this early stage, the chick neural plate is already regionalized and cells positioned at distinct rostrocaudal levels are specified to generate cells exhibiting a gene expression profile characteristic of the forebrain, midbrain, rostral hindbrain and caudal spinal cord, respectively. In addition, the Isthmic organizer (IsO), a secondary signaling centre at the midbrain–hindbrain border that is required for the further development of this region, is also specified already at the gastrula stage. Caudal neural character is induced by signals from adjacent tissues - the primitive streak and the paraxial mesoderm. Wingless/Wnts, Fibroblastic growth factors (FGFs) and retinoids (RA) are signaling molecules that have been proposed to promote caudal embryonic development, and exhibit spatio- emporal expression patterns that coincide with early caudalizing activities. The caudalizing activity that emanates from the gastrula stage paraxial mesoderm is mediated by Wnt signals, and the induction of caudal neural character by Wnts results from a direct action on neural precursor cells. In the presence of FGF activity, graded Wnt signaling is sufficient to induce cells exhibiting caudal forebrain, midbrain and rostral hindbrain character. The discrimination between rostral hindbrain and caudal spinal cord character appear to depend on a gradient of both Wnt and FGF signals.At hindbrain and spinal cord levels the patterned generation of neural progenitor cells along the rostrocaudal axis controls the generation of different classes of motor neurons in response to diffusible Sonic hedgehog (Shh) signals. Gastrula stage Wnt signaling is also required for this subsequent generation of motor neuron subtypes characteristic of the hindbrain and spinal cord.Later, at the early somite stage, cells characteristic of the caudal hindbrain and rostral spinal cord are specified adjacent to RA producing paraxial mesoderm. Opponent RA and FGF signals appear to act on, and refine the rostrocaudal identity of the initial hindbrain and spinal cord cells induced by gastrula stage Wnt based signals. Consistently, combinatorial Wnt, FGF and/or RA signals are sufficient to reconstruct neural progenitor cells that differentiate into motor neurons characteristic of the caudal hindbrain, rostral spinal cord and caudal spinal cord, respectively, in response to Shh.