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Molecular mechanisms of neurogenesis in the developing forebrain and peripheral nervous system

Posted by , on 27 July 2016

Closing Date: 15 March 2021

The laboratory of Developmental Genetics is looking for a PhD student to study the molecular mechanisms of neurogenesis in the developing mouse nervous system. The student will have to apply for a FNRS FRIA fellowship (http://www.fnrs.be/index.php/news-fnrs/517-fria-fresh-2016). The deadline for the application is the 30th August 2016.

The unit is located in the Biopark Charleroi Brussels South (http://ibmm.biopark-it.be/bced/), about 25 miles south of Brussels, in the Institute of Molecular Biology and Medecine (IBMM), a leading multidiciplinarity Institute from the faculty of Science and Medecine of the ULB (http://www.ulb.ac.be/rech/inventaire/unites/ULB578.html). The unit is part of the ULB Neuroscience Institute (http://uni.ulb.ac.be/groups/developmental-genetics/). The group is studying the molecular mechanisms that control the transition from neural stem cell to neurons in the developing vertebrate nervous system. The focus is on the role of some transcription factors in the molecular mechanisms that control neural progenitor maintenance, differentiation, and the generation of neuronal diversity. Major ongoing researches focus on the role of Dmrt transcription factors in cerebral cortex development and of Prdm transcription factors in pain perception, in health and diseases.
The laboratory uses in vivo genetic approaches in the mouse as well as gain- and loss-of-function experiments in the frog to approach gene function in the developing embryo.

The candidate will be involved in one of the two following projects:

Project A:

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments, and is therefore essential for survival. In human, erroneous activation of the pain-sensing system, as in chronic and neuropathic pain, represents a major health burden with insufficient treatment option. New therapeutic options have recently been developed from studies of a small number of individuals with Congenital Insensitivity to Pain (CIP). The majority of these have Mendelelian disorders of painlessness, where disruptive mutations in a single gene are responsible for their inability to sense pain.
Prdm12 has recently been identified as mutated in individuals with CIP (Chen et al., Nature Genet 47, 803-808, 2015). In our laboratory, we have obtained evidence that Prdm12 is crucial for the generation of the nociceptors, the type of neurons that sense noxious stimuli and transfer nociceptive information to the CNS (Nagy et al., Cell Cycle 14, 1799-1808, 2015). Prdm12 belongs to a family of evolutionarily conserved epigenetic regulators that control neuronal specification (Thélie et al., Development 142, 3416-3428, 2015). It is highly and selectively expressed in differentiating nociceptors and remains expressed in these cells post-natally, suggesting that modulating it may be a new route for pain control.
In this project, our aim is to elucidate Prdm12 mechanism of action in nociceptor differentiation during mammalian embryonic development and determine whether its activity also influences nociceptive function in the adulthood. These objectives will be approached through the detailed characterization of Prdm12 null knock-out and transgenic mice and cell lines available or under construction and using state-of-the art genomics, epigenetic, proteomic and electrophysiological approaches.

Projet B:

Understanding the mechanisms that control the generation of distinct types of neurons from multipotent progenitors constitute a major challenge in developmental neurosciences. Transcription factors are at the core of the programs that control cortical development. Two members of the Dmrt family of zinc finger transcription factors, Dmrt3-5, are expressed by cortical progenitors in a similar high caudomedial to low rostrolateral gradient. Our laboratory has shown that Dmrt5, whose mutation in human has been recently associated with microcephaly (Urquhart et al., Clinical Genetics, 2016) is essential for the development of the caudomedial part of the cerebral cortex including the hippocampus and that it plays a direct role in neocortical progenitors in the control of their specification (Saulnier et al., Cereb. Cortex 23, 2552-2567, 2013 ; De Clercq et al., submitted). Recent results of the laboratory indicate that Dmrt3 also contribute to cortical patterning. Despite their importance, the mode of action of Dmrt5 and Dmrt3 in the specification of cortical progenitor identity and in the control of cortical growth remains largely unknown.
In this project, our objective is to understand these mechanisms through the characterization of the phenotype of Dmrt5-/-;Dmrt3-/- double mutant mice and the identification of their in vivo genomic binding sites (using chromatin immunoprecipitation). These studies should provide important insights into the transcriptional mechanisms controling early cortical development.

PhD candidates should be highly motivated and have previous experience in mouse handling, neurobiology or molecular biology. Interested candidates should send their CV including a motivation letter and contact information of at least two previous supervisors able to recommend their research ability to ebellefr@ulb.ac.be

For more information, see our recent work:

Saulnier et al. (2013). The Doublesex Homolog Dmrt5 is Required for the Development of the Caudomedial Cerebral Cortex in Mammals. Cerebral Cortex, 23, 2552-2567.

Nagy V, Cole T, Van Campenhout C, Khoung TM, Leung C, Vermeiren S, Novatchkova M, Wenzel D, Cikes D, Polyansky AA, Kozieradzki I, Meixner A, Bellefroid EJ, Neely GG, Penninger JM. The evolutionarily conserved transcription factor (2015). PRDM12 controls sensory neuron development and pain perception. Cell Cycle. 14, 1799-808.

Thélie et al. (2015). Prdm12 specifies V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes in Xenopus. Development 142, 3416-3428.




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