Molecular determination of cerebellar GABAergic neuron specification

• Applicant: Dr. Luis R. Hernandez-Miranda, Ph.D.
• Subject Area: Developmental Neurobiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 512746157

The mature cerebellum controls our motor skills and participates in several brain functions that include learning, cognition, and speech. Congenital cerebellar malformations oftentimes lead to the lack of muscle movement coordination (known as ataxia), speech deficits, loss of body balance control or disorganized eye movements. Furthermore, abnormal cerebellar development can result in cerebellar hypoplasia, or hydrocephalus, and can also lead to many other neurological diseases that include autism and medulloblastoma. Given the enormous diversity and complexity of the central nervous system, our understanding on the molecular mechanisms that safeguard the development and function of its individual neuronal components is still largely incomplete. This project proposal aims to elucidate the transcriptional programs that direct the specification of GABAergic cerebellar neurons, these are the Purkinje cells and inhibitory interneurons. These neurons develop from Ptf1a-expressing progenitor cells in a defined temporal order, that is Purkinje cells first and inhibitory interneurons later. Our preliminary investigations have identified four transcription factors that play distinct temporal functions in the specification of both neuronal subtypes. The precise transcriptional programs regulated by these factors will be determined in this project. Public Health Relevance. This project will provide essential insights into the molecular programs regulating the development of cerebellar GABAergic neurons, the neuronal types more frequently affected in congenital cerebellar malformations. This work will thus produce a rich source of molecular data for clinicians, neuroscientists, and biomedical researchers focusing on the identification of molecular mechanisms associated with developmental dysfunction of the cerebellum.

• DFG Programme: Research Grants