Insm1 controls development of pituitary endocrine cells and requires a SNAG domain for function and for recruitment of histone-modifying factors

Welcker, Jochen; Hernández-Miranda, Luis R.; Paul, Fabian; Jia, Shiqi; Ivanov, Andranik; Selbach, Matthias; Birchmeier, Carmen

doi:10.1242/dev.097642

Cited by 48 publications

(53 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This finding is consistent with a previous study identifying RCOR1/2 in complexes with INSM1 in an endocrine cell line (24). Another study detected Insm1 transcripts in abventricular neural progenitors and nascent neurons (25).…”

Section: Discussionsupporting

confidence: 93%

“…But in the cases where these factors have been deleted from the developing brain in mice (18,22,23), the phenotypes did not resemble those of Rcor1/2 KOs. One exception was the transcriptional repressor INSM1, which has been identified in complexes with RCOR1/2 in an endocrine cell line (24), is expressed in late neural progenitors (25), and has a germline knockout phenotype that resembles that of the Rcor1/2 KO (26). However, no functional link has been established between RCOR1/RCOR2 and INSM1 in the developing nervous system.…”

Section: Rcor1/2 Kos Have More Neural Progenitors But Fewer Neurons Andmentioning

confidence: 99%

See 1 more Smart Citation

REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation–differentiation balance in the developing brain

Monaghan

Nechiporuk

Jeng

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The transcriptional events that lead to the cessation of neural proliferation, and therefore enable the production of proper numbers of differentiated neurons and glia, are still largely uncharacterized. Here, we report that the transcription factor Insulinoma-associated 1 (INSM1) forms complexes with RE1 Silencing Transcription factor (REST) corepressors RCOR1 and RCOR2 in progenitors in embryonic mouse brain. Mice lacking both RCOR1 and RCOR2 in developing brain die perinatally and generate an abnormally high number of neural progenitors at the expense of differentiated neurons and oligodendrocyte precursor cells. In addition, Rcor1/2 deletion detrimentally affects complex morphological processes such as closure of the interganglionic sulcus. We find that INSM1, a transcription factor that induces cell-cycle arrest, is coexpressed with RCOR1/2 in a subset of neural progenitors and forms complexes with RCOR1/2 in embryonic brain. Further, the Insm1 −/− mouse phenocopies predominant brain phenotypes of the Rcor1/2 knockout. A large number of genes are concordantly misregulated in both knockout genotypes, and a majority of the down-regulated genes are targets of REST. Rest transcripts are up-regulated in both knockouts, and reducing transcripts to control levels in the Rcor1/2 knockout partially rescues the defect in interganglionic sulcus closure. Our findings indicate that an INSM1/RCOR1/2 complex controls the balance of proliferation and differentiation during brain development.he development of the nervous system is an intricately orchestrated series of events beginning with formation of neuroepithelia. Progenitors that emerge from neuroepithelial stem cells undergo several proliferative transitions before ceasing to divide and terminally differentiating into neurons and glia. Both maintenance of the proliferative state and terminal transition to differentiated neurons and glia are regulated, in part, by chromatin-modifying proteins that are recruited to genes by specific transcription factors. In many cases, however, chromatin-modifying proteins have only been studied in vitro, and their roles in vivo remain unknown. For example, a protein whose importance in epigenetic regulation of neural genes has been recognized is RE1 Silencing Transcription factor (REST) Corepressor 1 (RCOR1) (1, reviewed in ref. 2). RCOR1 was identified originally as a direct binding partner for the master transcriptional regulator of neural genes, REST (3-5). The REST/RCOR1 complex has been studied primarily in cultured stem/progenitor cells, neurons, and glia (6-9). Like many other adaptor proteins in transcriptional complexes, RCOR1 does not have intrinsic enzymatic activity but rather binds directly to chromatin-modifying enzymes including histone deacetylases 1 and 2 (HDAC1/2) and the histone demethylase KDM1A (LSD1) (10-12). A related protein, RCOR2, shares ∼90% homology with RCOR1 in the ELM2 and SANT functional domains (13) and is also found in complexes with KDM1A and HDAC1/2 (14). Furthermore, RCOR2 is recruited by some of t...

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Rcor1/2 Kos Have More Neural Progenitors But Fewer Neurons Andmentioning

confidence: 99%

REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation–differentiation balance in the developing brain

Monaghan

Nechiporuk

Jeng

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The following primary antibodies and dilution were used: mouse anti-Ascl1 at 1:200 (BD #556604), guinea-pig anti-Ascl1 at 1:10,000 (Kim et al, 2008), mouse anti-beta III tubulin at 1:5000 (Chemicon #MAB1637), goat anti-BhlhB5 at 1:1000 (Santa Cruz #sc-6045), rabbit or rat anti-BhlhB5 at 1:2000 (Ross et al, 2012), sheep anti-Chx10 (Vsx2) at 1:500 (Exalpha Biologicals #X1179P), goat anti Dll4 at 1:200 (R&D System #AF1389), rabbit or guinea pig anti-Foxd3 at 1:5000 (Müller et al, 2005), rat anti-Gata3 at 1: 20 (Panayi et al, 2010), guinea-pig anti-Insm1 at 1:10,000 (Welcker et al, 2013), mouse anti-Islet 1/2 at 1:6000 (DSHB #39.4D5), mouse anti-Lhx3 at 1:1000 (DSHB #67.4E12), mouse anti-Lhx1/5 at 1:2000 (DSHB # 4F2), rat anti-Nkx6.1 at 1:2 (Ono et al, 2007), guinea pig anti-OC-1 at 1:6000 (Espana and Clotman, 2012), sheep anti-OC-1 at 1:250 (R&D System #AF6277), rat anti-OC-2 at 1:400 (Clotman et al, 2005), mouse anti-p27 kip1 at 1:2000 (BD), mouse anti-Pax6 at 1:1000 (DSHB #PAX6), mouse anti-phospho-Histone H3 at 1:1000 (Abcam ab14955), rabbit or guinea pig anti-Prdm8 at 1:1000 (Ross et al, 2012), goat anti-Prox1 at 1:100 (R&D Systems # AF2727), mouse anti-Shox2 at 1:500 (Abcam #ab55740), goat anti-Sox 1 at 1:500 (Santa Cruz #sc-17318), rabbit anti-Vsx1 at 1:500 (Clark et al, 2008). …”

Section: Methodsmentioning

confidence: 99%

Vsx1 Transiently Defines an Early Intermediate V2 Interneuron Precursor Compartment in the Mouse Developing Spinal Cord

Francius

Hidalgo-Figueroa

Debrulle

et al. 2016

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Spinal ventral interneurons regulate the activity of motor neurons, thereby controlling motor activities. Interneurons arise during embryonic development from distinct progenitor domains distributed orderly along the dorso-ventral axis of the neural tube. A single ventral progenitor population named p2 generates at least five V2 interneuron subsets. Whether the diversification of V2 precursors into multiple subsets occurs within the p2 progenitor domain or involves a later compartment of early-born V2 interneurons remains unsolved. Here, we provide evidence that the p2 domain produces an intermediate V2 precursor compartment characterized by the transient expression of the transcriptional repressor Vsx1. These cells display an original repertoire of cellular markers distinct from that of any V2 interneuron population. They have exited the cell cycle but have not initiated neuronal differentiation. They coexpress Vsx1 and Foxn4, suggesting that they can generate the known V2 interneuron populations as well as possible additional V2 subsets. Unlike V2 interneurons, the generation of Vsx1-positive precursors does not depend on the Notch signaling pathway but expression of Vsx1 in these cells requires Pax6. Hence, the p2 progenitor domain generates an intermediate V2 precursor compartment, characterized by the presence of the transcriptional repressor Vsx1, that contributes to V2 interneuron development.

show abstract

“…However, in neural stem cells, CoREST targets a group of genes which are not REST targets, suggesting other relevant mechanisms in neuronal specification (6,7). A variety of transcription factors have indeed been shown to interact with CoREST and/or LSD1/KDM1A, thus bringing the LCH complex to transiently repress or silence target genes in both neuronal and nonneuronal systems (8,9). For instance, in hematopoietic cells, the zinc finger transcription factor Gfi (growth factor independent) recruits CoREST to regulate the expression of target genes during erythroid differentiation (9,10).…”

mentioning

confidence: 99%

Differential Properties of Transcriptional Complexes Formed by the CoREST Family

Barrios

Gómez

Sáez

et al. 2014

Molecular and Cellular Biology

View full text Add to dashboard Cite

dMammalian genomes harbor three CoREST genes. rcor1 encodes CoREST (CoREST1), and the paralogues rcor2 and rcor3 encode CoREST2 and CoREST3, respectively. Here, we describe specific properties of transcriptional complexes formed by CoREST proteins with the histone demethylase LSD1/KDM1A and histone deacetylases 1 and 2 (HDAC1/2) and the finding that all three CoRESTs are expressed in the adult rat brain. CoRESTs interact equally strongly with LSD1/KDM1A. Structural analysis shows that the overall conformation of CoREST3 is similar to that of CoREST1 complexed with LSD1/KDM1A. Nonetheless, transcriptional repressive capacity of CoREST3 is lower than that of CoREST1, which correlates with the observation that CoREST3 leads to a reduced LSD1/KDM1A catalytic efficiency. Also, CoREST2 shows a lower transcriptional repression than CoREST1, which is resistant to HDAC inhibitors. CoREST2 displays lower interaction with HDAC1/2, which is barely present in LSD1/KDM1A-CoREST2 complexes. A nonconserved leucine in the first SANT domain of CoREST2 severely weakens its association with HDAC1/2. Furthermore, CoREST2 mutants with increased HDAC1/2 interaction and those without HDAC1/2 interaction exhibit equivalent transcriptional repression capacities, indicating that CoREST2 represses in an HDAC-independent manner. In conclusion, differences among CoREST proteins are instrumental in the modulation of protein-protein interactions and catalytic activities of LSD1/KDM1A-CoREST-HDAC complexes, fine-tuning gene expression regulation.

show abstract

Insm1 controls development of pituitary endocrine cells and requires a SNAG domain for function and for recruitment of histone-modifying factors

Cited by 48 publications

References 56 publications

REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation–differentiation balance in the developing brain

REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation–differentiation balance in the developing brain

Vsx1 Transiently Defines an Early Intermediate V2 Interneuron Precursor Compartment in the Mouse Developing Spinal Cord

Differential Properties of Transcriptional Complexes Formed by the CoREST Family

Contact Info

Product

Resources

About