MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors

Abstract

During cerebellum development, Sonic hedgehog (Shh)-induced proliferation of cerebellar granular neuronal precursors (CGNPs) is potently inhibited by bone morphogenetic proteins (BMPs). We have previously reported the upregulation of TIEG-1 and Mash1, two antimitotic factors that modulate MYCN transcription and N-Myc activity, in response to BMP2. To gain further insight into the BMP antimitotic mechanism, we used microRNA (miRNA) arrays to compare the miRNAs of CGNPs proliferating in response to Shh with those of CGNPs treated with Shh plus BMP2. The array analysis revealed that miRNA 11 (miR-22) levels significantly increased in cells treated with BMP2. Additionally, in P7 mouse cerebellum, miR-22 distribution mostly recapitulated the combination of BMP2 and BMP4 expression patterns. Accordingly, in CGNP cultures, miR-22 overexpression significantly reduced cell proliferation, whereas miR-22 suppression diminished BMP2 antiproliferative activity. In contrast to BMP2, miR-22 did not induce neural differentiation but instead significantly increased cell cycle length. Consistent with the central role played by N-myc on CGNP proliferation, Max was revealed as a direct target of miR-22, and miR-22 expression caused a significant reduction of Max protein levels and N-myc/Max-dependent promoter activity. Therefore, we conclude that, in addition to the previously described mechanisms, miR-22 plays a specific role on downstream BMPs through cerebellum growth.

MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1

“…Within the nervous system, the miR-22 family has been reported to participate in neuroprotection (Yu et al, 2015; Jovicic et al, 2013), neurodegeneration (Lee et al, 2011), neuroinflammation (Parisi et al, 2013; Siegel et al, 2012), neurodevelopment (Volvert et al, 2014; Berenguer et al, 2013), and neuroplasticity (Chen et al, 2013). Thus, although this family appears to have multiple roles in the nervous system and disease, our current studies identify members of this family as specifically involved in the suppression of memory formation.…”

Development of the cerebellum: simple steps to make a ‘little brain’

“…For example, non-canonical Wnt signalling via Wnt3 has recently been shown to be capable of decreasing proliferation independently of BMP signalling (Anne et al, 2013). Conversely, multiple BMPs are expressed in the cerebellum during EGL development and can antagonise the Shh-dependent proliferation of granule progenitors both in vitro and in slice cultures (Rios et al, 2004) through regulation of Atoh1 (Zhao et al, 2008) and via miR22 (Berenguer et al, 2013). Conditional deletions of intracellular mediators of Box 3.…”

Mitotic Events in Cerebellar Granule Progenitor Cells That Expand Cerebellar Surface Area Are Critical for Normal Cerebellar Cortical Lamination in Mice

“…Antagonizing CGNP proliferation, either extrinsically by decreasing SHH signaling (7), or by intrinsically affecting CGNP proliferation (13), results in secondary Purkinje cell dyslamination. SHH -induced CGNP proliferation is physiologically blocked by cyclic AMP activation or by treatment with basic fibroblast growth factor and bone morphogenetic protein 2 (8, 18), presumably by antagonizing SHH signaling (19). Such mechanisms of blocking SHH -mediated proliferation ultimately decrease the number of symmetrical divisions of CGNPs, promoting the cells to exit cell cycle and migrate down Bergman glial filaments into the internal granule layer (IGL).…”