Title: Investigating cerebellar GABAergic cell specification in a novel recessive syndrome with cerebellar hypoplasia and hypogonadotropic hypogonadism.
Funder: The Academy of Medical Sciences

Abstract: My over-all aim is to understand how defects in GABAergic fate specification in the developing cerebellum contribute to neurodevelopmental disorders. I will achieve this by constructing the first detailed map of cerebellar GABAergic differentiation in mice using genetic inducible fate mapping and single cell transcriptomics. I recently identified a key role for a novel epigenetic regulator, PRDM13 in early steps of GABAergic cell fate specification. Thus, I propose to dissect the role of PRDM13 in GABAergic fate determination. PRDM13 mutation is linked to a novel recessive syndrome with hypogonadatropic hypogonadism, cerebellar hypoplasia, delayed motor development and intellectual disability. I will: (1) Perform comprehensive morphological and molecular spatiotemporal analyses of cerebellar GABAergic neurons. I will combine state of the art genetic fate mapping with analysis of known and putative (using mouse sc-RNA seq analyses) GABAergic specific markers to identify novel GABAergic neuronal populations and specification genes. (2) Investigate the functional role of Prdm13 in cerebellar development. PRDM proteins regulate gene expression therefore histological and transcriptomic analysis of Prdm13 mutant mice will be used to identify key putative genetic regulators of interneuron specification. (3) Investigate how cerebellar GABAergic neurons and specification factors have diverged and expanded in humans. Outcomes of (1) and (2) will be compared with human studies performed by collaborators to identify conserved and unique human GABAergic cerebellar neurons and putative specification genes. Together, these studies will identify novel putative regulators of GABAergic neurogenesis. Factors identified as conserved or unique to human cerebellar development will be prioritised for functional studies.

Lay abstract: There are around 90 billion neurons in the human brain, which are all generated during development from a small pool of cells that respond to signals that instruct them to form different types of brain cells (neurons). One of the fundamental questions of neuroscience is how and which genes give instructions during development to drive these cells to form different neuronal populations. This proposal developed after three children presented with intellectual disability and delayed motor development, typical of cerebellar dysfunction, and no recognised medical diagnosis. Further investigations revealed (i) via advanced brain imaging that the cerebellum, an area of the brain important for motor coordination and learning, was smaller than usual and (ii) via genetic testing that there was a mutation in a gene called PRDM13. We performed studies in mice that showed that Prdm13 is responsible for generating important neurons in the cerebellum, GABAergic interneurons; there are multiple different types in the cerebellum and they are particularly important in fine-tuning information processing. Very little is known about how this diverse population is formed in early development. Prdm13 is one of the first identified factors that appears to control this process. I will investigate how Prdm13 influences interneuron development. More widely I will use new genetic tools to dissect how cerebellar GABAergic interneurons are formed and initiate collaborative work to do the same in human brain samples. These studies will allow us to eventually perform functional studies to understand how mutations affecting GABAergic cell fate may lead to neurological disease.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL