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MicroRNA-independent functions of DGCR8 are critically required for neocortical development and TBR1 expression

ABSTRACT: Recent evidence indicates that DROSHA, DGCR8 and DICER exert non-overlapping functions, including miRNA-independent regulatory mechanisms. It is currently unknown whether miRNA-independent functions of DGCR8 play any role in corticogenesis. Here, by phenotypic comparison of conditional knockout cortices for Dgcr8 and Dicer, we uncover that Dgcr8 deletion, in contrast to Dicer, leads to premature differentiation of neural progenitor cells and overproduction of Tbr1 positive neurons. Remarkably, miRNA depletion does not account for these phenotypic differences, indicating that miRNA-independent functions of DGCR8 are critical for corticogenesis. We propose Tbr1 transcript, bearing evolutionary conserved hairpins that resemble miRNA precursors, as one of DGCR8 targets. Our study uncovers, for the first time in the nervous system, an earlier and stronger phenotype occurring in Dgcr8 compared to Dicer mutant and proposes that this effect is mediated by miRNA-independent functions of DGCR8.

ORGANISM(S): Mus musculus

PROVIDER: GSE82069 | GEO | 2017/02/17

SECONDARY ACCESSION(S): PRJNA323920

REPOSITORIES: GEO

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Stabilizing Heterochromatin by DGCR8 Alleviates Senescence and Osteoarthritis

Project description:DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and attenuating aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its miRNA-processing activity, which is mediated by its C-terminal domains. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1 Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathologically and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA processing-independent role for DGCR8 in maintaining heterochromatin organization and attenuating senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.

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DGCR8 HITS-CLIP reveals novel functions for the Microprocessor (CLIP-seq)

2012-07-15 | E-GEOD-39086 | biostudies-arrayexpress

Genome wide identification of targets of the drosha-pasha/DGCR8 complex

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