Abstract
ABSTRACTMigration and organization of the nucleus are essential for the proliferation and differentiation of cells, including neurons. However, the relationship between the positioning of the nucleus and cellular morphogenesis remains poorly understood. Inherited recessive cerebellar ataxia has been attributed to mutations in SYNE1, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. Regardless, Syne1-mutant mice present with normal cerebellar development. The Sad1-Unc-84 homology (SUN)-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 of Sun1 showed a 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. Results of immunohistochemical analyses suggested that Sun1 is highly expressed in Purkinje cells and recruits Syne2 to the periphery of the nucleus. 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), whereas the proliferation and migration of granule neurons were unaffected. Furthermore, the Sun1−/−Sun2+/− Purkinje cells exhibited retarded primary dendrite specification, reduced dendritic complexity and aberrant patterning of synapses. Our findings reveal a cell-type-specific role for Sun1 and Sun2 in nucleokinesis during cerebellar development, and we propose the use of Sun-deficient mice as a model for studying cerebellar ataxia that is associated with mutation of human SYNE genes or loss of Purkinje cells.
Highlights
The positioning of the nucleus affects the proliferation, migration and differentiation of neurons (Higginbotham and Gleeson, 2007; Morris et al, 1998; Zhang et al, 2009)
In this study, the authors generated genetically modified mice that lack Sun1 and/or Sun2 in different allelic combinations, and they report that Sun1 and Sun2 contribute to the development of murine cerebellum
Implications and future directions This study shows that Sun1 and Sun2 play an important role during cerebellar development, in particular in regulating nucleokinesis in Purkinje cells
Summary
The positioning of the nucleus affects the proliferation, migration and differentiation of neurons (Higginbotham and Gleeson, 2007; Morris et al, 1998; Zhang et al, 2009). Two processes that affect the movement of neurons are interkinetic nuclear migration and nucleokinesis (Burke and Roux, 2009). Nucleokinesis involves movement of the neuron in three steps: neurite extension, migration of the microtubule organization center (MTOC) and repositioning of the nucleus (Tsai and Gleeson, 2005). Both interkinetic nuclear migration and nucleokinesis require proper coordination and connection with the cytoskeletal structure and the nucleus for accurate nuclear positioning. Understanding the mechanisms that initiate, maintain and terminate neuronal migration is key to mapping brain circuitry, and to gaining insight into both normal and pathological neurodevelopment (Ghashghaei et al, 2007)
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