C1QL1 REGULATES GRANULE CELL PRECURSORS PROLIFERATION AND DIFFERENTIATION IN THE DEVELOPING CEREBELLUM

Cerebellar granule cells (GCs) are the most abundant neuronal population in the mammalian brain, accounting for approximately 99% of cerebellar neurons. Their development occurs mainly during late embryonic and early postnatal stages in humans, and during the first postnatal weeks in mice. GC development relies on the precise regulation of proliferation, differentiation, and maturation of granule cell precursors (GCPs), a process controlled by intrinsic genetic programs and extrinsic trophic factors such as Sonic Hedgehog (SHH) and BDNF, which are key drivers of neuronal differentiation.
C1QL1 is a secreted protein of the C1q-related family expressed by several glial and neuronal populations in the brain. It has been shown to regulate synapse specification between climbing fibers and Purkinje cells during olivocerebellar circuit development by interacting with the adhesion GPCR Brain Angiogenesis Inhibitor 3.
Using Fluorescent In Situ Hybridization, genetic lineage tracing, and genetically modified mouse models, we show that C1QL1 is also highly expressed in proliferating GCPs within the external granular layer during early postnatal development. To investigate its function in these cells, we characterized a constitutive C1ql1 knockout mouse generated by CRISPR/Cas9.
By tracking the transition from GCPs to differentiated GCs using state-specific markers, we observed a significant increase in the GCP population accompanied by a reduction in mature granule neurons in the absence of C1QL1. Together, our results identify C1QL1 as a modulator of granule cell development, suggesting that it restricts GCP proliferation while promoting cell cycle exit and differentiation, thereby maintaining the balance between proliferation and differentiation.