Abstract
The small nuclear ribonucleoprotein polypeptide N (SNRPN) gene, encoding the RNA-associated SmN protein, duplications or deletions of which are strongly associated with neurodevelopmental disabilities. SNRPN-coding protein is highly expressed in the brain. However, the role of SNRPN protein in neural development remains largely unknown. Here we showed that the expression of SNRPN increased markedly during postnatal brain development. Overexpression or knockdown of SNRPN in cortical neurons impaired neurite outgrowth, neuron migration, and the distribution of dendritic spines. We found that SNRPN regulated the expression level of Nr4a1, a critical nuclear receptor during neural development, in cultured primary cortical neurons. The abnormal spine development caused by SNRPN overexpression could be fully rescued by Nr4a1 co-expression. Importantly, we found that either knockdown of Nr4a1 or 3, 3′- Diindolylmethane (DIM), an Nr4a1 antagonist, were able to rescue the effects of SNRPN knockdown on neurite outgrowth of embryonic cortical neurons, providing the potential therapeutic methods for SNRPN deletion disorders. We thus concluded that maintaining the proper level of SNRPN is critical in cortical neurodevelopment. Finally, Nr4a1 may serve as a potential drug target for SNRPN-related neurodevelopmental disabilities, including Prader-Willi syndrome (PWS) and autism spectrum disorders (ASDs).
Highlights
The small nuclear ribonucleoprotein polypeptide N (SNRPN) gene, encoding the RNA-binding SmN protein, is located within chromosome 15q11-q13 in the region associated with various neurodevelopmental disabilities such as Prader-Willi syndrome (PWS), Angelman syndrome (AS) and autism spectrum disorders (ASDs)[1,2,3]
SmN expressed at a low level in the embryonic cerebral cortex and increased approximately 5-fold during brain development (Fig. 1a,d)
The expression profile of SNRPN was similar to that seen in the cerebral cortex (Fig. 1c,d)
Summary
The small nuclear ribonucleoprotein polypeptide N (SNRPN) gene, encoding the RNA-binding SmN protein, is located within chromosome 15q11-q13 in the region associated with various neurodevelopmental disabilities such as Prader-Willi syndrome (PWS), Angelman syndrome (AS) and autism spectrum disorders (ASDs)[1,2,3]. These neurodevelopmental disorders are often associated with various degrees of autistic behavior and learning disabilities. The results demonstrate that abnormal expression of SNRPN impairs neurological function through regulating Nr4a1 and Nr4a1 represents a potential therapeutic target for SNRPN-associated diseases
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