Roles of Onecut factors in spinal dorsal interneuron and in sensory neuron development

Sensory experience is encoded by specific neurons located both in the peripheral and in the central nervous systems to integrate and elicit adequate responses. Sensory neurons, the cell bodies of which reside in dorsal root ganglia (DRG), relay input such as pain, temperature, itch, touch and limb and muscle length. This information is largely integrated and relayed in the spinal cord. During development, distinct neuronal types, including sensory neurons and dorsal interneurons (dIN), differentiate from progenitors into neurons characterized by distinct molecular identities, localizations and connectivity. However, the molecular mechanisms that control those processes remain incompletely characterized. Previous data obtained in our laboratory have shown that the Onecut (OC) transcription factors are present in sensory neurons and in several spinal dIN populations. This suggests that these factors could contribute to the regulation of the sensory neuron and spinal dIN development. My thesis goal is to study OC roles during these processes and to elucidate the underlying molecular mechanisms in the spinal cord. In this work, I provide evidence that the OC factors are necessary for proper diversification of dI5 interneurons and migration of early-born dIN populations. Moreover, I highlight that the OC factors control the expression of spinal Pou2f2. Using gain- or loss-of-function experiments, we show that Pou2f2 contributes to the regulation of dIN distribution. Also, I show that OC factors regulate early differentiation and segregation of distinct sensory subsets. Furthermore, OC are required for proper positioning and for normal projections of sensory neurons into the spinal cord or towards their peripheral targets. Thus, we uncover mechanisms of action of OC proteins in the regulation of spinal dIN development and OC involvement in sensory neuron differentiation, positioning and axonal projections during embryonic development.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

Pou2f2 Regulates the Distribution of Dorsal Interneurons in the Mouse Developing Spinal Cord.

Spinal dorsal interneurons, which are generated during embryonic development, relay and process sensory inputs from the periphery to the central nervous system. Proper integration of these cells into neuronal circuitry depends on their correct positioning within the spinal parenchyma. Molecular cues that control neuronal migration have been extensively characterized but the genetic programs that regulate their production remain poorly investigated. Onecut (OC) transcription factors have been shown to control the migration of the dorsal interneurons (dINs) during spinal cord development. Here, we report that the OC factors moderate the expression of , a transcription factor essential for B-cell differentiation, in spinal dINs. Overexpression or inactivation of leads to alterations in the differentiation of dI2, dI3 and Phox2a-positive dI5 populations and to defects in the distribution of dI2-dI6 interneurons. Thus, an OC-Pou2f2 genetic cascade regulates adequate diversification and distribution of dINs during embryonic development

The Onecut Transcription Factors Regulate Differentiation and Distribution of Dorsal Interneurons during Spinal Cord Development

During embryonic development, the dorsal spinal cord generates numerous interneuron populations eventually involved in motor circuits or in sensory networks that integrate and transmit sensory inputs from the periphery. The molecular mechanisms that regulate the specification of these multiple dorsal neuronal populations have been extensively characterized. In contrast, the factors that contribute to their diversification into smaller specialized subsets and those that control the specific distribution of each population in the developing spinal cord remain unknown. Here, we demonstrate that the Onecut transcription factors, namely Hepatocyte Nuclear Factor-6 (HNF-6) (or OC-1), OC-2 and OC-3, regulate the diversification and the distribution of spinal dorsal interneuron (dINs). Onecut proteins are dynamically and differentially distributed in spinal dINs during differentiation and migration. Analyzes of mutant embryos devoid of Onecut factors in the developing spinal cord evidenced a requirement in Onecut proteins for proper production of a specific subset of dI5 interneurons. In addition, the distribution of dI3,dI5 and dI6 interneuron populations was altered. Hence, Onecut transcription factors control genetic programs that contribute to the regulation of spinal dIN diversification and distribution during embryonic development

Onecut Factors and Pou2f2 Regulate the Distribution of V2 Interneurons in the Mouse Developing Spinal Cord

Acquisition of proper neuronal identity and position is critical for the formation of neural circuits. In the embryonic spinal cord, cardinal populations of interneurons diversify into specialized subsets and migrate to defined locations within the spinal parenchyma. However, the factors that control interneuron diversification and migration remain poorly characterized. Here, we show that the Onecut transcription factors are necessary for proper diversification and distribution of the V2 interneurons in the developing spinal cord. Furthermore, we uncover that these proteins restrict and moderate the expression of spinal isoforms of Pou2f2, a transcription factor known to regulate B-cell differentiation. By gain- or loss-of-function experiments, we show that Pou2f2 contribute to regulate the position of V2 populations in the developing spinal cord. Thus, we uncovered a genetic pathway that regulates the diversification and the distribution of V2 interneurons during embryonic development