Nuclear migration and organization are essential for the proliferation and differentiation of cells, including neurons. However, the relationship between nuclear positioning and cellular morphogenesis remains poorly understood. Inherited recessive cerebellar ataxia has been attributed to mutations in SYNE1, a component of the LINC (linker of nucleoskeleton and cytoskeleton) complex. Regardless, Syne1 mutant mice present normal cerebellar development. The SUN (Sad1-Unc-84 homology)-domain proteins are located at the inner nuclear membrane and recruit SYNE proteins through the KASH domain to the outer nuclear membrane. Here we report an unrecognized contribution of Sun1 and Sun2 to the postnatal development of murine cerebellum. Mice depleted for Sun1 showed marked reduction in the cerebellar volume, and this phenotype is exacerbated with additional loss of a Sun2 allele. Consistent with these histological changes, Sun1-/- and Sun1-/-Sun2+/- mice exhibited defective motor coordination. The immunohistochemical result suggested that Sun1 is highly expressed in Purkinje cells and recruits Syne2 to the nuclear periphery. Approximately 33% of Purkinje cells in Sun1-/- mice and 66% of Purkinje cells in Sun1-/-Sun2+/- mice were absent from the surface of the internal granule layer (IGL), while the proliferation and migration of granule neurons were unaffected. Furthermore, the Sun1-/-Sun2+/- Purkinje cells presented retarded primary dendrite specification, reduced dendritic complexity, and aberrant patterning of synapses. Our findings revealed a cell type-specific role for Sun1/2 in nucleokinesis during cerebellar development, and propose the application of Sun-deficient mice as a model for studying Purkinje cell loss- and human SYNE- associated cerebellar ataxia.
Date:
2015-08
Relation:
Disease Models and Mechanisms. 2015 Aug;8(8):957-967.
