Book Description

The diverse cell types of the vertebrate central nervous system, neurons and glial cells, are generated during embryonic development by neural progenitors that differentiate in a highly specific manner both in space and time. Remarkably, the generation of these two diverse cell types is temporally separated with neurons being generated first and glial cells being generated later. The molecular mechanisms controlling neural cell fate diversification are well defined in the developing spinal cord. In the ventral embryonic spinal cord, the secreted protein Sonic hedgehog (Shh), produced source cells at the ventral midline, is the main morphogen factor inducing neural cell fate diversification. Shh diffuses from its source and establishes a concentration gradient in the target tissue that induces the apparition of distinct neural progenitor domains in a dose-dependent manner. Each one of these domains expresses a specific transcriptional code and produces a specific type of neural cells. Particularly, ventral-most neural progenitors, included in the p3 domain, express the transcription factor Nkx2.2 and generate V3 interneurons whereas dorsally located neural progenitors of the pMN domain express the transcription factor Olig2 and generate motoneurons. Importantly, the establishment of these two domains occurs progressively. Olig2 is first induced in the ventral part of the developing tissue in response to low doses of Shh. At a second time point, Nkx2.2 is up-regulated in ventral-most neural progenitors in response to higher doses of Shh. This transcription factor further down-regulates Olig2 in these cells giving rise to the two adjacent p3 and pMN domains. Interestingly, at stage of glial specification, a temporal increase in Shh activity leads to spatial rearrangement in gene expression domains in this region. A novel domain, called p*, is formed following up-regulation of Nkx2.2 expression in Olig2-expressing progenitors. Co-expression of these transcription factors, which is maintained at this stage, triggers these progenitors to generate oligodendrocyte precursors (OPCs). A key player in this process is Sulfatase1 (Sulf1) that has been previously identified in the group as an essential temporal regulator of Shh activity at the time of OPC specification. It belongs to the family of extracellular endosulfatases which edit post-synthetically the sulfation profile of heparan sulfate proteoglycans (HSPGs), components of the extracellular matrix, and thus modulate HSPGs interaction with a great variety of signalling molecules. During my Ph.D., I used mainly zebrafish as a model to address the role and mode of action of Sulf1 in the temporal control of Shh activity during neural development in the ventral spinal cord. We found that Sulf1 is required for accurate temporal activation of Shh-dependent high-threshold target gene nkx2.2a early during initial pattern establishment and later during pattern rearrangement which permits the generation of V3 interneurons and OPCs, respectively. Importantly, we found that Sulf1 is reiteratively up-regulated in Shh producing cells at these two distinct stages of neural development. Furthermore, we provide evidence that Sulf1 up-regulation promotes the provision of a biologically active form of Shh from its source allowing the induction of high-threshold response to Shh. In conclusion, our results demonstrate that Sulf1 is an essential temporal regulator of Shh activity during spinal cord development. Our results highlight a novel mode of temporal regulation of morphogen factor activity during development in which temporal changes in morphogen activity are mediated by temporal evolution in the morphogen source properties.