miR-125b promotes cell death by targeting spindle assembly checkpoint gene MAD1 and modulating mitotic progression

The spindle assembly checkpoint (SAC) is a ‘wait-anaphase'' mechanism that has evolved in eukaryotic cells in response to the stochastic nature of chromosome–spindle attachments. In the recent past, different aspects of the SAC regulation have been described. However, the role of microRNAs in the SAC is vaguely understood. We report here that Mad1, a core SAC protein, is repressed by human miR-125b. Mad1 serves as an adaptor protein for Mad2 – which functions to inhibit anaphase entry till the chromosomal defects in metaphase are corrected. We show that exogenous expression of miR-125b, through downregulation of Mad1, delays cells at metaphase. As a result of this delay, cells proceed towards apoptotic death, which follows from elevated chromosomal abnormalities upon ectopic expression of miR-125b. Moreover, expressions of Mad1 and miR-125b are inversely correlated in a variety of cancer cell lines, as well as in primary head and neck tumour tissues. We conclude that increased expression of miR-125b inhibits cell proliferation by suppressing Mad1 and activating the SAC transiently. We hypothesize an optimum Mad1 level and thus, a properly scheduled SAC is maintained partly by miR-125b.     

Molecular and Synaptic Bases of CDKL5 Disorder

The X‐linked gene cyclin‐dependent kinase‐like 5 (CDKL5) encodes a serine/threonine kinase abundantly expressed in the brain. Mutations in CDKL5 have been associated with neurodevelopmental disorders characterized by early‐onset epileptic encephalopathy and severe intellectual disability, suggesting that CDKL5 plays important roles in brain development and function. Recent studies using cultured neurons, knockout mice, and human iPSC‐derived neurons have demonstrated that CDKL5 regulates axon outgrowth, dendritic morphogenesis, and synapse formation. The role of CDKL5 in maintaining synaptic function in the mature brain has also begun to emerge. Moreover, mouse models that are deficient for CDKL5 recapitulate some of the key clinical phenotypes in human patients. Here we review these findings related to the function of CDKL5 in the brain and discuss the underlying molecular and cellular mechanisms.     

The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction

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