Arginine Methylation Regulates MEIS2 Nuclear Localization to Promote Neuronal Differentiation of Adult SVZ Progenitors

Abstract

SummaryAdult neurogenesis is regulated by stem cell niche-derived extrinsic factors and cell-intrinsic regulators, yet the mechanisms by which niche signals impinge on the activity of intrinsic neurogenic transcription factors remain poorly defined. Here, we report that MEIS2, an essential regulator of adult SVZ neurogenesis, is subject to posttranslational regulation in the SVZ olfactory bulb neurogenic system. Nuclear accumulation of MEIS2 in adult SVZ-derived progenitor cells follows downregulation of EGFR signaling and is modulated by methylation of MEIS2 on a conserved arginine, which lies in close proximity to nested binding sites for the nuclear export receptor CRM1 and the MEIS dimerization partner PBX1. Methylation impairs interaction with CRM1 without affecting PBX1 dimerization and thereby allows MEIS2 nuclear accumulation, a prerequisite for neuronal differentiation. Our results describe a form of posttranscriptional modulation of adult SVZ neurogenesis whereby an extrinsic signal fine-tunes neurogenesis through posttranslational modification of a transcriptional regulator of cell fate.

MEIS transcription factors in development and disease

“…The presence of NES and NLS motifs in the MEIS and PBX polypeptides suggests that both proteins can shuttle between nucleus and cytoplasm (Fig. 2B) (Kolb et al, 2018). Control over their subcellular localization thus provides a simple but effective mechanism to regulate the activity of this protein group.…”

“…Interestingly, the NES in the MEIS polypeptide is fully embedded in the PBX-binding surface (Knoepfler et al, 1997). Consequently, binding of MEIS to either PBX or the nuclear export receptor chromosomal maintenance 1/exportin 1 (CRM1/ XPO1) must be mutually exclusive events, which provides a parsimonious mechanism to regulate the subcellular localization of MEIS proteins (Kolb et al, 2018). Conversely, MEIS1 promotes nuclear localization and stabilizes PBX1 in the limb bud and hindbrain of vertebrate embryos (Mercader et al, 1999;Waskiewicz et al, 2001), and the PBX homolog extradenticle (exd) requires heterodimerization with Hth for nuclear import in D. melanogaster (Abu-Shaar et al, 1999;Rieckhof et al, 1997).…”

“…Conversely, MEIS1 promotes nuclear localization and stabilizes PBX1 in the limb bud and hindbrain of vertebrate embryos (Mercader et al, 1999;Waskiewicz et al, 2001), and the PBX homolog extradenticle (exd) requires heterodimerization with Hth for nuclear import in D. melanogaster (Abu-Shaar et al, 1999;Rieckhof et al, 1997). Although codependency of PBX and MEIS transcription factors for nuclear accumulation is seen in many different developmental contexts, this process itself can be regulated by post-translational modification: serine phosphorylation of PBX1 circumvents its dependency on MEINOX proteins for nuclear localization, while arginine methylation of MEIS2 decreases its affinity for CRM1 (Kilstrup-Nielsen et al, 2003;Kolb et al, 2018). This modification interferes with MEIS2 nuclear export, favors its heterodimerization with PBX1 in the cell nucleus, and thereby ensures stable nuclear accumulation of the MEIS2 protein (Fig.…”

“…Although the N terminus does not seem to possess any biochemical activity, the C terminus harbors a transcriptional activation domain (Huang et al, 2005;Hyman-Walsh et al, 2010). MEINOX family proteins also possess a nuclear export signal (NES) and the TALE-HD is N-terminally flanked by a stretch of basic amino acids that, as in many HD-containing transcription factors, can serve as nuclear localization signal (NLS) (Kolb et al, 2018) (Fig. 2A).…”

A Systematic Analysis Revealed the Potential Gene Regulatory Processes of ATRA-Triggered Neuroblastoma Differentiation and Identified a Novel RA Response Sequence in theNTRK2Gene

“…or neurodegenerative diseases has been reported in previous studies. e TFs encoded by FOXJ3, HOXD1, MEIS2, NEF2L2, NFIB, and STAT5 have been reported to be involved in the mechanism of neuronal differentiation or contribute to maintain neuron function [50][51][52][53][54][55][56].…”