FGF9 knockout in GABAergic neurons induces apoptosis and inflammation via the Fas/caspase-3 pathway in the cerebellum of mice

Abstract

Fibroblast growth factor 9 (FGF9) is a member of the fibroblast growth factor family and is widely expressed in the central nervous system (CNS). However, it is not clear how the working mechanism of FGF9 is involved in cerebellar development. To address this question, we deleted the Fgf9 gene specifically in GABAergic neurons or glutamatergic neurons, and demonstrated that Fgf9 ablation in GABAergic neurons rather than the glutamatergic neurons caused severe ataxia. We showed that FGF9 played a key role in the survival and development of Purkinje cells. GABAergic neuron-specific knockout of FGF9 (Fgf9^VGAT) significantly affected the survival and development of Purkinje cells, disrupting Bergmann fiber scaffold formation and granule neuron migration in mice. RNA sequencing revealed that 976 differentially expressed genes (DEGs) were identified between Fgf9^VGAT and control mice. The DEGs with significantly upregulated expression were found to be involved in apoptotic and inflammatory signaling. Selected genes including Fas, Bid, Mapk11, Cxcl10, CCl2, Bik and Fos, were validated by qRT-PCR and exhibited increases in expression in Fgf9^VGAT mice compared to control mice similar to those seen in the RNA-sequencing data. The expression levels of apoptosis- and inflammation-related proteins were also increased, especially those of Fas and caspase-3 pathway related proteins. Interestingly, activated ERK signaling has been observed in apoptosis and inflammatory responses induced by deleting Fgf9 in GABAergic neurons.

Keywords: Apoptosis; Ataxia; FGF9; Purkinje cells.