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Genetic control of cell diversification into neuronal subtypes

Final Activity Report Summary - NEURONAL SUBTYPES (Genetic Control of Cell Diversification into Neuronal Subtypes)

Cell fate decisions and phenotypic differentiation emerge from the signalling by local organising centres and target fields, resulting in intrinsic transcriptional programmes directing cell fate commitment. The concerted action of such programmes in different cells is what generates the cellular complexity that characterises vertebrate organisms. Knowledge on how this is achieved is naturally a central and important task in the area of life sciences. During my post-doc training at the Karolinska Institute, I took advantage of an interdisciplinary set of state of the art technologies in order to address how cell diversity was created in the peripheral nervous system and, more generally, in neural crest stem cells.

In a first study, I demonstrated that:

1. the sensory system was, at least partially, intrinsically determined with respect to the functional diversification of the sensory neurons
2. the sensory neurons were phenotypically distinct along the rostro-caudal axis of the body, a finding which had high impact on the physiological outcome
3. a restricted set of transcription factors, namely the Runx family, directed peripheral and central extension of sensory axons during development.

By the time of the project completion I was working to identify the upstream regulators of the expression of Runx transcription factors, which were determining the fate of neuronal cell types in the sensory system. Overall, this research opened for a new area of investigation in neurosciences. It was also anticipated to contribute with new knowledge in the field of therapeutic cell replacement strategies and for enhancing treatment of debilitating nerve injuries in the clinical setting.

During a second study, I aimed at understanding when, where and how neural crest cells, which generated neurons and glial cells of the peripheral nervous system, melanocytes, smooth muscle cells, connective tissue and cartilaginous and skeletal elements in the head, were committed to a specific cell type during development. Although in the field scientific community felt to be in the position of understanding the basics of neural crest cell differentiation, our research presented some startling new evidence for the existence of a hitherto undiscovered mode of melanocyte generation. Our new data suggested that melanocytes were not exclusively produced by late migrating neural crest cells, but rather that a substantial number arose from Schwann cell precursors associated with extending nerves. We were further able to identify some of the signals emanating from the nerve that could play a role in regulating this fate choice.

Our study was significant as it gave us profound new insights into the origin of melanocytes and, more generally, neural crest cells. It overturned our previous view that melanocytes were exclusively generated by a distinct population of neural crest cells, namely those that migrated last, and that these cells were committed to a melanogenic fate just after delamination from the neural tube. It rather seemed that the process of melanocyte differentiation was more complex and plastic. This study also highlighted the importance of Schwann cell precursors as the source of both glial cells and melanocytes. This could help to explain the association between alteration in skin pigmentation and neurological disorders, such as the ones observed in patients with neurofibromatosis type 1.