Generation of neuronal diversity by temporal mechanisms in the developing spinal cord

• Applicant: Dr. Andreas Sagner
• Subject Area: Developmental Neurobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455354162

In the vertebrate spinal cord different classes of neurons form the neuronal circuits that allow us to move and perceive our environment. During development, these distinct classes of neurons are generated in response to spatial cues that pattern the embryonic neural tube along its dorsal-ventral axis. This subdivision however is not sufficient to account for the complexity of neurons observed in the spinal cord - instead each neuronal class can be further divided into distinct subtypes based on molecular and functional characteristics. The signals and gene regulatory networks that orchestrate the specification of these neuronal subtypes and underlie their correct incorporation into circuits with specific functions are still largely unclear.My recent work uncovered a temporal dimension to neuronal subtype specification in the spinal cord, which depends on cohorts of transcription factors (TFs) that are specific for early, intermediate, or late-born neurons. Here, I propose that this temporal TF program is essential and works in combination with the spatial TFs that define the identity of the distinct neuronal classes to establish neuronal diversity and the correct patterns of neuronal connectivity in the spinal cord. To test this hypothesis, I plan to combine in vitro stem cell differentiation with genomic assays, in vivo genetic tracing and functional perturbation approaches. The key aims of this proposal are to:1. Characterize the signals and gene regulatory networks orchestrating the temporal stratification of neurons in the spinal cord,2. Investigate the molecular logic by which spatial and temporal TFs jointly establish neuronal subtype-specific patterns of gene Expression, 3. Delineate how temporal TF expression in the embryo underlies neuronal diversity and connectivity in the adult spinal cord. The expected results of my proposal will provide a detailed understanding how spatial and temporal patterning systems jointly specify neuronal diversity and underlie the correct formation of neuronal circuitry in the mouse spinal cord. Ultimately, such mechanistic understanding of cell fate and connectivity will underpin the development of novel disease models and therapies for neurodegenerative movement disorders and spinal injuries.

• DFG Programme: Independent Junior Research Groups
• International Connection: United Kingdom
• Cooperation Partner: Dr. Andrew Murray