Craniofacial abnormalities resulting from targeted disruption of the murine <i>Sim2</i> gene

Shamblott, Michael J.; Bugg, Elizabeth M.; Lawler, Ann M.; Gearhart, John D.

doi:10.1002/dvdy.10116

Cited by 54 publications

(46 citation statements)

References 26 publications

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“…Targeted deletion of SIM2 in mice results in scoliosis, major disruptions in craniofacial structures and death shortly after birth owing to a breathing defect (Goshu et al, 2002;Shamblott et al, 2002), which shows that it has important roles during development. Alternative splicing produces a short (SIM2s) protein variant in mice and humans (Chrast et al, 1997;Metz et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

Farrall

Whitelaw

2009

Oncogene

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The short isoform of single-minded 2 (SIM2s), a basic helix-loop-helix/PAS (bHLH/PAS) transcription factor, is upregulated in pancreatic and prostate tumours; however, a mechanistic role for SIM2s in these cancers is unknown. Microarray studies in prostate DU145 cells identified the pro-cell death gene, BNIP3 (Bcl-2/adenovirus E1B 19 kDa interacting protein 3), as a novel putative target of SIM2s repression. Further validation showed BNIP3 repression in several prostate and pancreatic carcinoma-derived cell lines with ectopic expression of human SIM2s. BNIP3 levels are enhanced in prostate carcinoma cells upon short interfering (si)RNA-mediated knockdown of endogenous SIM2s. Chromatin immunoprecipitation and promoter studies show that SIM2s represses BNIP3 through its activities at the proximal promoter hypoxia response element (HRE), the site through which the bHLH/PAS family member, hypoxia-inducible factor 1a (HIF1a), induces BNIP3. SIM2s attenuates BNIP3 hypoxic induction via the HRE, and increased hypoxic induction of BNIP3 occurs with siRNA knockdown of endogenous SIM2s in prostate PC3AR þ cells. BNIP3 is implicated in hypoxia-induced cell death processes. Prolonged treatment of PC3AR þ cells with hypoxia mimetics, DP and DMOG, confers hypoxia-induced autophagy, measured by enhanced LC3-II levels and SQSTM1/p62 turnover. We show that PC3AR þ cells expressing ectopic SIM2s have enhanced survival in these conditions. Induction of LC3-II and turnover of SQSTM1/p62 are attenuated in PC3AR þ / SIM2s DMOG and hypoxia-treated cells, suggesting that SIM2s may attenuate autophagic cell death processes, perhaps through BNIP3 repression. These data show, for the first time, SIM2s cross-talk on an endogenous HRE. SIM2s' functional interference with HIF1a activities on BNIP3 may indicate a novel role for SIM2s in promoting tumourigenesis.

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Section: Introductionmentioning

confidence: 99%

The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

Farrall

Whitelaw

2009

Oncogene

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“…Despite the loss of one repression domain, SIM2s has been shown to repress directly target gene transcription in different cellular models (Kwak et al, 2007;Laffin et al, 2008;Woods et al, 2008;Farrall and Whitelaw, 2009;Wellberg et al, 2010). Sim2 mutant mice die perinatally owing to lung atelectasis and breathing failure, but display multiple other phenotypes such as rib, vertebrae and craniofacial abnormalities (Goshu et al, 2002;Shamblott et al, 2002). The only muscle phenotype described in the absence of Sim2 activity in mouse mutants is a diaphragm hypoplasia at birth (Goshu et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Sim2 prevents entry into the myogenic program by repressing MyoD transcription during limb embryonic myogenesis

et al. 2012

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SUMMARYThe basic helix-loop-helix transcription factor MyoD is a central actor that triggers the skeletal myogenic program. Cellautonomous and non-cell-autonomous regulatory pathways must tightly control MyoD expression to ensure correct initiation of the muscle program at different places in the embryo and at different developmental times. In the present study, we have addressed the involvement of Sim2 (single-minded 2) in limb embryonic myogenesis. Sim2 is a bHLH-PAS transcription factor that inhibits transcription by active repression and displays enhanced expression in ventral limb muscle masses during chick and mouse embryonic myogenesis. We have demonstrated that Sim2 is expressed in muscle progenitors that have not entered the myogenic program, in different experimental conditions. MyoD expression is transiently upregulated in limb muscle masses of Sim2 -/-mice.Conversely, Sim2 gain-of-function experiments in chick and Xenopus embryos showed that Sim2 represses MyoD expression. In addition, we show that Sim2 represses the activity of the mouse MyoD promoter in primary myoblasts and is recruited to the MyoD core enhancer in embryonic mouse limbs. Sim2 expression is non-autonomously and negatively regulated by the dorsalising factor Lmx1b. We propose that Sim2 represses MyoD transcription in limb muscle masses, through Sim2 recruitment to the MyoD core enhancer, in order to prevent premature entry into the myogenic program. This MyoD repression is predominant in ventral limb regions and is likely to contribute to the differential increase of the global mass of ventral muscles versus dorsal muscles.

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“…Efforts to manipulate the EB environment and subsequent ES cell differentiation have focused primarily on either controlling media composition (Schuldiner et al 2000) or assembly of EBs using different culture methods (Hopfl et al 2004). The three basic methods are: (i) Hanging drop (HD) (Shamblott et al 2002) (Chen et al 2010), (ii) static suspension culture (SSC) (Dang et al 2002) and (iii) bioreactors bioreactors (Yirme et al 2008). The latter technique can be divided further to different rotary cell culture system (RCCS) technologies which is comprised of a slow turning lateral vessel (STLV) and a high aspect rotating vessel (HARV) (Gerecht-Nir et al 2004;Lu, et al 2008;Hwang et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Enhanced cardiac differentiation of mouse embryonic stem cells by use of the slow-turning, lateral vessel (STLV) bioreactor

et al. 2011

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To cite this version:Sasitorntime of EB adherence to gelatin-coated dishes, and rotation speed for optimal EB formation and cardiac differentiation were investigated. Using 3x10 5 cells/ml, 10 rpm rotary speed and plating of EBs onto gelatin-coated surfaces three days after culture, were the best parameters for optimal size and EB quality on consequent cardiac differentiation. These optimized parameters enrich cardiac differentiation in ES cells when using the STLV method.

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Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene

Cited by 54 publications

References 26 publications

The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

Sim2 prevents entry into the myogenic program by repressing MyoD transcription during limb embryonic myogenesis

Enhanced cardiac differentiation of mouse embryonic stem cells by use of the slow-turning, lateral vessel (STLV) bioreactor

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