Meis2 is a Pax6 co-factor in neurogenesis and dopaminergic periglomerular fate specification in the adult olfactory bulb

Abstract

Meis homeodomain transcription factors control cell proliferation, cell fate specification and differentiation in development and disease. Previous studies have largely focused on Meis contribution to the development of non-neuronal tissues. By contrast, Meis function in the brain is not well understood. Here, we provide evidence for a dual role of the Meis family protein Meis2 in adult olfactory bulb (OB) neurogenesis. Meis2 is strongly expressed in neuroblasts of the subventricular zone (SVZ) and rostral migratory stream (RMS) and in some of the OB interneurons that are continuously replaced during adult life. Targeted manipulations with retroviral vectors expressing function-blocking forms or with small interfering RNAs demonstrated that Meis activity is cell-autonomously required for the acquisition of a general neuronal fate by SVZ-derived progenitors in vivo and in vitro. Additionally, Meis2 activity in the RMS is important for the generation of dopaminergic periglomerular neurons in the OB. Chromatin immunoprecipitation identified doublecortin and tyrosine hydroxylase as direct Meis targets in newly generated neurons and the OB, respectively. Furthermore, biochemical analyses revealed a previously unrecognized complex of Meis2 with Pax6 and Dlx2, two transcription factors involved in OB neurogenesis. The full proneurogenic activity of Pax6 in SVZ derived neural stem and progenitor cells requires the presence of Meis. Collectively, these results show that Meis2 cooperates with Pax6 in generic neurogenesis and dopaminergic fate specification in the adult SVZ-OB system. KEY WORDS: Pax6, TALE-homeodomain proteins, Adult neurogenesis, Subventricular zone, Mouse INTRODUCTIONThe subventricular zone (SVZ), located between the lateral ventricle and the striatum, and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus are major stem cell niches in the adult

Meis1 coordinates a network of genes implicated in eye development and microphthalmia

“…Alternatively, Meis1 could interact with a wide variety of TFs in the eye, including its own putative targets such as Sox2, Pax6 and Otx2, reinforcing their activity. The latter possibility is supported by the observation that the related Meis2 has been shown to interact at least with Otx2, Pax3, Pax6 and Pax7 (Agoston et al, 2014(Agoston et al, , 2012Agoston and Schulte, 2009). Alternatively, and based on the predominant presence of a 'Meis1-only' targeted sequence (m1, Fig.…”

Pbx1 is required for adult SVZ neurogenesis

“…Of the Tuj1-expressing neuroblasts in the SVZ or RMS, 81.75±13.2% were immunoreactive for PBX1 and virtually all of these co-labeled for MEIS2 (Fig. 1G-I) (Agoston et al, 2014). Notably, the dentate gyrus of the hippocampus, which is the second major stem cell niche in the adult mouse brain, is devoid of Pbx1 transcripts or protein (Fig.…”

“…Mechanistically, PBX1 associates with members of the MEIS/PREP subclass of TALE-HD proteins, but can also form heteromeric complexes with HOX proteins, non-HOX HD-containing proteins, bHLH or PAX proteins (Ladam and Sagerström, 2014;Longobardi et al, 2014;). As we have recently shown, MEIS2 is an essential co-factor of the neurogenic transcription factor PAX6 and as such is required for the acquisition of a general neuronal fate in the SVZ and the subsequent differentiation of a subpopulation of these cells towards dopaminergic periglomerular neurons (Agoston et al, 2014;Brill et al, 2008;Hack et al, 2005;Kohwi et al, 2005Kohwi et al, , 2007.…”

A Brn2–Zic1 axis specifies the neuronal fate of retinoic-acid-treated embryonic stem cells

“…Motif co-occurrence analysis (Fig. 2F) revealed an enriched association between the MORE or MORE+1 sites and motifs for various factors, such Meis transcription factors, which are important in neurogenesis (Agoston et al, 2014;Yamada et al, 2013), the DR1 motif for the Rar-Rxr or Pparg-Rxr heterodimers, and Runx1 and Foxd3. There is, however, selectivity as MORE sites associate with motifs for other nuclear receptors, notably the DR5 for Rar-Rxr, and sites for Nr5a2 and Nr2f1 (Coup-Tf1), as well as for Trp53 and Trp63, whereas MORE+1 sites are associated with motifs targeted by Tead1 and Rest, both of which have known functions in neurogenesis (Ballas and Mandel, 2005;Cao et al, 2008).…”