The neurodevelopmental process is orchestrated

The neurodevelopmental process is orchestrated by a series of intrinsic mechanisms and extrinsic cues. Among these, intrinsic epigenetic regulation plays an important role in neural progenitor fate specification and provides one explanation about the complexity of developmental processes. DNA methylation in the form of 5-methylcytosine (5mC) is essential for normal development in mammals and influences a variety of biological processes, including transcriptional regulation, imprinting, and the maintenance of genomic stability. Hydroxymethylcytosine is emerging as the active demethylation modification that targets a specific 5-methyl group on cytosine for net removal by a complex EPZ-6438 excision repair mechanism (Guo et al., 2011a, 2011b). Consistent with the idea that hydroxymethylcytosine is involved as a specific mechanism for active cytosine demethylation, recent studies identified the ten-eleven translocation (TET) family of proteins in active DNA demethylation (Ito et al., 2010; Tahiliani et al., 2009). The three mammalian TET proteins, TET1, TET2, and TET3, have changed our understanding of the process of DNA demethylation as they can oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) (He et al., 2011; Ito et al., 2010; Tahiliani et al., 2009). Recent studies have shown that TET-mediated DNA demethylation can play vital roles in various biological processes, not only in development but also in disease. Despite these advances, the functions of TET proteins and their regulation in brain development need further investigation. Here, we report the unique roles of MCPIP1 during early neocortical development. We found a dramatic expression pattern of MCPIP1 during early cortical neurogenesis. MCPIP1 regulates various aspects of neurogenesis. Notably, we observed that MCPIP1 directly targets Tets, and represses TET and 5hmC expression levels. Importantly, the interaction of MCPIP1 and TETs is involved in neurogenesis and NPC pool maintenance. Our current data demonstrate a direct and important molecular link between the immune regulatory molecule, TETs, and epigenetic regulation.
Results
Discussion Although the brain has traditionally been regarded as immune-privileged, many studies suggest that there is extensive communication between the immune system and the nervous system in both healthy and diseased conditions. We sought here to learn about the basic roles of specific and crucial immune molecules in the nervous system. We observed that MCPIP1 was abundant in early neural progenitors and that its expression decreased over time during early mouse neocortical development. In the murine cortex, neurogenesis begins at approximately E12, reaches a peak at approximately E15, and terminates at approximately E18 (Qian et al., 2000). Therefore, MCPIP1 expression in the developing neocortex suggested precise temporal and spatial roles for MCPIP1 during this period. We identified these roles by demonstrating that altered Mcpip1 expression resulted in changes of various aspects of neurogenesis. Notably, the composition of the neural progenitor pool was altered following Mcpip1 expression variation, resulting in a change in the relative proportion of apical progenitors to basal progenitors. A potentially interesting possibility was explored, showing that MCPIP1 inhibited apical progenitor generation but promoted its transition. Next, we investigated the underlying mechanism for MCPIP1 in early cortical neurogenesis. It is known that active DNA demethylation is prevalent in mammals (Tan and Shi, 2012). TET proteins were recently identified as enzymes that promote DNA demethylation (Ito et al., 2010; Tahiliani et al., 2009). Direct regulation of Tet expression should be a rather straightforward means of modulating the level of DNA modification. Although regulation of Tet expression at the transcriptional level is well documented (Fu et al., 2013; Song et al., 2013), insights into the direct regulation of Tet mRNA by an RNA-binding protein are reported herein.