Abstract
The cerebellum is conceptualized as a processor of complex movements. Many diseases with gene-targeted mutations, including Fahr’s disease associated with the loss-of-function mutation of meningioma expressed antigen 6 (Mea6), exhibit cerebellar malformations, and abnormal motor behaviors. We previously reported that the defects in cerebellar development and motor performance of Nestin-Cre;Mea6F/F mice are severer than those of Purkinje cell-targeted pCP2-Cre;Mea6F/F mice, suggesting that Mea6 acts on other types of cerebellar cells. Hence, we investigated the function of Mea6 in cerebellar granule cells. We found that mutant mice with the specific deletion of Mea6 in granule cells displayed abnormal posture, balance, and motor learning, as indicated in footprint, head inclination, balanced beam, and rotarod tests. We further showed that Math1-Cre;Mea6F/F mice exhibited disrupted migration of granule cell progenitors and damaged parallel fiber-Purkinje cell synapses, which may be related to impaired intracellular transport of vesicular glutamate transporter 1 and brain-derived neurotrophic factor. The present findings extend our previous work and may help to better understand the pathogenesis of Fahr’s disease.
Highlights
The cerebellum has been conceptualized as a processor of complex movements and is endowed with essential roles in cognitive and emotional behaviors (Su et al, 2020)
Our results showed that the deletion of Meningioma expressed antigen 6 (Mea6) in granule cells led to severe motor symptoms during the posture, balance, and motor learning tests
We found that tdTomato fluorescence was present merely in the cerebellum of these mice (Figure 1B), suggesting that the knockout mediated by Math1-recombinase is specific in the cerebellum
Summary
The cerebellum has been conceptualized as a processor of complex movements and is endowed with essential roles in cognitive and emotional behaviors (Su et al, 2020). This study provides limited insights on how Mea plays roles in CNS development because Nestin-driven Cre recombinase inevitably affects all types of neural cells in the CNS. We report distinct cerebellar development and motor performance between Nestin-Cre;Mea6F/F and Purkinje cell-targeted pCP2-Cre;Mea6F/F mice (Wang et al, 2019). While Nestin-Cre;Mea6F/F mice have shrunken cerebellum and lobules, pCP2-Cre;Mea6F/F mice merely display extensive self-crossings of Purkinje cell dendrites without changing cyto-architecture of the cerebellum (Wang et al, 2019). These results suggest that Mea influences the development of other types of cerebellar cells beyond Purkinje cells
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