Expression of Groucho/TLE proteins during pancreas development

Hoffman, Brad G.; Zavaglia, Bogard; Beach, Mike; Helgason, Cheryl D.

doi:10.1186/1471-213x-8-81

Cited by 28 publications

(34 citation statements)

References 56 publications

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“…In the pancreas, Grg2 and Grg3 are coexpressed with Nkx2.2 Hoffman et al 2008), and Grg3 interacts with Nkx2.2 via the conserved TN domain ). To determine whether the physical interaction between Nkx2.2 and Grg proteins is necessary for appropriate pancreatic islet development and/or function, we generated mice that express a mutant allele of Nkx2.2 containing amino acid substitutions within the core sequence of the TN domain (Nkx2.2 TNmut/TNmut ) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The ability of Nkx2.2 to act as a transcriptional repressor in the developing pancreas has also been shown ). Grg2 and Grg3, rather than Grg4, are coexpressed with Nkx2.2 in the pancreas and can also interact with Nkx2.2 through the groucho interaction TN domain Hoffman et al 2008). In this study, we mutated the Nkx2.2 TN domain to determine the role of Grg-mediated Nkx2.2 repressor activity in the developing pancreas.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Nkx2.2 repressor complex regulates islet β-cell specification and prevents β-to-α-cell reprogramming

Papizan¹,

Singer²,

Tschen³

et al. 2011

Genes Dev.

188

187

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Regulation of cell differentiation programs requires complex interactions between transcriptional and epigenetic networks. Elucidating the principal molecular events responsible for the establishment and maintenance of cell fate identities will provide important insights into how cell lineages are specified and maintained and will improve our ability to recapitulate cell differentiation events in vitro. In this study, we demonstrate that Nkx2.2 is part of a large repression complex in pancreatic b cells that includes DNMT3a, Grg3, and HDAC1. Mutation of the endogenous Nkx2.2 tinman (TN) domain in mice abolishes the interaction between Nkx2.2 and Grg3 and disrupts b-cell specification. Furthermore, we demonstrate that Nkx2.2 preferentially recruits Grg3 and HDAC1 to the

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nkx2.2 repressor complex regulates islet β-cell specification and prevents β-to-α-cell reprogramming

Papizan¹,

Singer²,

Tschen³

et al. 2011

Genes Dev.

188

187

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“…Arx overexpression in Activin A-treated a-cells prevents the reduction to cell proliferation but not the repression of Gcg expression in pancreatic a-cells [Mamin and Philippe, 2007]. Another study has examined the interaction of Groucho/Tle transcriptional corepressors with transcription factors important in the endocrine pancreas [Hoffman et al, 2008]. This study proposes roles for Groucho/Tle corepressors acting upon many transcription factors involved in endocrine pancreas development, including Neurog3.…”

Section: Arx Function In the Endocrine Pancreasmentioning

confidence: 99%

“…This study proposes roles for Groucho/Tle corepressors acting upon many transcription factors involved in endocrine pancreas development, including Neurog3. In particular, Tle2 was shown to interact with Arx and in b-cells this corepressor modulates the repressive capacity of Arx transcriptional activity [Hoffman et al, 2008].…”

Section: Arx Function In the Endocrine Pancreasmentioning

confidence: 99%

ARX spectrum disorders: making inroads into the molecular pathology

2010

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The Aristaless-related homeobox gene (ARX) is one of the most frequently mutated genes in a spectrum of X-chromosome phenotypes with intellectual disability (ID) as their cardinal feature. To date, close to 100 families and isolated cases have been reported to carry 44 different mutations, the majority of these (59%) being a result of polyalanine tract expansions. At least 10 well-defined clinical entities, including Ohtahara, Partington, and Proud syndromes, X-linked infantile spasms, X-linked lissencephaly with ambiguous genitalia, X-linked myoclonic epilepsy and nonsyndromic intellectual disability have been ascertained from among the patients with ARX mutations. The striking intra- and interfamilial pleiotropy together with genetic heterogeneity (same clinical entities associated with different ARX mutations) are becoming a hallmark of ARX mutations. Although males are predominantly affected, some mutations associated with malformation phenotypes in males also show a phenotype in carrier females. Recent progress in the study of the effect of ARX mutations through sophisticated animal (mice) and cellular models begins to provide crucial insights into the molecular function of ARX and associated molecular pathology, thus guiding future inquiries into therapeutic interventions.

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“…Grg3 was found to repress liver genes such as albumin in the endoderm, restraining liver specification until the Grg3 protein was extinguished. Conversely, Grg3 is highly expressed in the pancreas during embryonic development (Doyle et al, 2007;Hoffman et al, 2008). RNA in situ analysis in the pancreas demonstrated that Grg3 is expressed at much higher levels than other Grg family members, Grg1, Grg2 and Grg4 (Doyle et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The transcriptional co-repressor Grg3/Tle3 promotes pancreatic endocrine progenitor delamination and β-cell differentiation

et al. 2012

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SUMMARYPancreatic -cells arise from Ngn3 + endocrine progenitors within the trunk epithelium of the embryonic pancreas. The emergence of endocrine cells requires E-cadherin downregulation, but the crucial steps that elicit such are not clear, yet probably important for ultimately being able to efficiently generate -cells de novo from stem cells. Grg3 (groucho-related gene 3, also known as Tle3), encodes a member of the Groucho/TLE family of co-repressors and its function in various cell contexts is mediated by recruitment to target genes by different transcription factors. Grg proteins broadly regulate the progression of progenitor cells to differentiated cell types, but specific developmental mechanisms have not been clear. We find that Grg3 is expressed in most -cells and a subset of other endocrine cell types in the pancreas. Grg3 is highly expressed in Ngn3 + endocrine progenitor descendants just after transient Ngn3 expression. Grg3-null embryos die at E14.5, which is associated with placental defects, so we explanted E12.5 pancreata to allow endocrine differentiation to occur in culture. Grg3 knockout explants displayed a drastic decrease in the differentiation of all endocrine cell types owing to defects in the delamination of early endocrine progenitors from the trunk epithelium. We find that Grg3 normally suppresses E-cadherin gene expression, thereby allowing delamination of endocrine cells from the trunk epithelium and revealing how this transcriptional co-repressor modulates this crucial step of -cell development.

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Expression of Groucho/TLE proteins during pancreas development

Cited by 28 publications

References 56 publications

Nkx2.2 repressor complex regulates islet β-cell specification and prevents β-to-α-cell reprogramming

Nkx2.2 repressor complex regulates islet β-cell specification and prevents β-to-α-cell reprogramming

ARX spectrum disorders: making inroads into the molecular pathology

The transcriptional co-repressor Grg3/Tle3 promotes pancreatic endocrine progenitor delamination and β-cell differentiation

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