The RNA-binding protein MARF1 promotes cortical neurogenesis through its RNase activity domain

Abstract

Cortical neurogenesis is a fundamental process of brain development that is spatiotemporally regulated by both intrinsic and extrinsic cues. Although recent evidence has highlighted the significance of transcription factors in cortical neurogenesis, little is known regarding the role of RNA-binding proteins (RBPs) in the post-transcriptional regulation of cortical neurogenesis. Here, we report that meiosis arrest female 1 (MARF1) is an RBP that is expressed during neuronal differentiation. Cortical neurons expressed the somatic form of MARF1 (sMARF1) but not the oocyte form (oMARF1). sMARF1 was enriched in embryonic brains, and its expression level decreased as brain development progressed. Overexpression of sMARF1 in E12.5 neuronal progenitor cells promoted neuronal differentiation, whereas sMARF1 knockdown decreased neuronal progenitor differentiation in vitro. We also examined the function of sMARF1 in vivo using an in utero electroporation technique. Overexpression of sMARF1 increased neuronal differentiation, whereas knockdown of sMARF1 inhibited differentiation in vivo. Moreover, using an RNase domain deletion mutant of sMARF1, we showed that the RNase domain is required for the effects of sMARF1 on cortical neurogenesis in vitro. Our results further elucidate the mechanisms of post-transcriptional regulation of cortical neurogenesis by RBPs.

Human MARF1 is an endoribonuclease that interacts with the DCP1:2 decapping complex and degrades target mRNAs

“…We show that MARF1 physically interacts with the DCP1:DCP2 RNA decapping complex and utilizes its PIN-like NYN endonuclease domain to degrade target mRNAs. In addition to its expression in the mammalian germline, MARF1 is also expressed in somatic tissues, including in the developing cortex where its expression has been reported to promote neuronal differentiation (16). Importantly, a MARF1 N-terminal truncation mutant that lacks the NYN domain could not promote neurogenesis.…”

“…MARF1-null oocytes accumulate Ppp2cb mRNA, the catalytic beta subunit of the major cellular phosphatase PP2A, and specific retrotransposon RNAs, including L ong in terspersed e lements (LINE1) RNA. In addition to its expression in the mammalian germline, MARF1 is also expressed in somatic tissues, including in the developing cerebral cortex where it has been reported to promote neuronal differentiation (16). Notwithstanding the critical role MARF1 plays in mammalian oogenesis, the molecular mechanism underpinning MARF1 function is not understood.…”

LOTUS-domain proteins - developmental effectors from a molecular perspective

“…An aromatic cage, as shown for the Tudor eTud domain in complex with an sDMA-modified Aub peptide (green), is absent from Tejas. (Kanemitsu et al 2017), suggesting that the underlying molecular mechanisms might be similar to those in oocytes.…”

“…Interestingly, the function of MARF1 seems not to be limited to the germline. In the developing mouse brain, a somatic isoform of MARF1 is expressed as a result of alternative splicing, causing an insertion of 179 amino acid residues within the N-terminal region (Kanemitsu et al 2017;Su et al 2012a) (Figure 1). Somatic MARF1 promotes the differentiation of cortical neuronal progenitor cells (Kanemitsu et al 2017), but exactly how is currently not understood.…”

Transcriptional and Post-Transcriptional Mechanisms of the Development of Neocortical Lamination

“…Overexpression of the somatic form of Marf1 at E13.5 resulted in increased Satb2+ neurons (corticocortical projection neurons) at postnatal day 2, though did not impact overall lamination, suggesting premature terminal differentiation. Marf1 was found to function through a somewhat unique mechanism: repression of transcripts through its RNAse activity (Kanemitsu et al, 2017 ), further demonstrating the wide range of activity that RBPs can have.…”