Mammalian cerebellar development is thought to be directed by distinct Purkinje cell (PC) subtypes. However, the degree of PC heterogeneity and its underlying molecular mechanisms remain poorly understood, limiting our ability to manipulate PC diversification and determine its role in cerebellar development. Through single-cell RNA sequencing, we identified at least 11 PC subtypes in the embryonic mouse cerebellum. We developed an unsupervised method to map these subtypes in three-dimensional space, revealing discrete PC subtypes predictive of adult cerebellar organization, including longitudinal stripes and lobules. These subtypes exhibit unique combinations of Foxp1, Foxp2, and Foxp4 expression. Deletion of Foxp2 and Foxp1 disrupts PC diversification, leading to altered cerebellar patterning, including the loss of a specific Foxp1- expressing subtype and the cerebellar hemisphere. Comparative analysis reveals that the FOXP1-expressing PC subtype is abundant in the fetal human cerebellum but rare in the chicken cerebellum, highlighting the significance of FOXP1-expressing PCs in cerebellar hemisphere development and evolution. Our findings demonstrate the critical role of Foxp genes in cerebellar development by regulating PC diversification.
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FOXP Genes Regulate Purkinje Cell Diversity in Cerebellar Development and Evolution
Nagham Khouri-Farah, Qiuxia Guo, Thomas A. Perry, Ryan Dussault, and James Y.H. Li (2024)