Endodermal expression of Nkx6 genes depends differentially on Pdx1

Pedersen, Jesper Karup; Nelson, Shelley B.; Jørgensen, Mette C.; Henseleit, Korinna; Fujitani, Yoshio; Wright, Chris; Sander, Maike; Serup, Palle

doi:10.1016/j.ydbio.2005.10.001

Cited by 84 publications

(92 citation statements)

References 45 publications

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“…Another contributing mechanism is the up-regulation of the transcription factor Nkx6.1, which is involved in the control of glucose-stimulated insulin secretion in pancreatic ␤ cells (18). It is possible that the BLK-induced increase in protein levels of Pdx-1 directly promotes the expression of Nkx6.1 (19) and the 2 transcription factors together enhance ␤-cell function and mass (20).…”

Section: Discussionmentioning

confidence: 99%

Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction

Borowiec

Liew

Thompson

et al. 2009

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

158

117

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Maturity-onset diabetes of the young (MODY) is a subtype of diabetes defined by an autosomal pattern of inheritance and a young age at onset, often before age 25. MODY is genetically heterogeneous, with 8 distinct MODY genes identified to date and more believed to exist. We resequenced 732 kb of genomic sequence at 8p23 in 6 MODY families unlinked to known MODY genes that showed evidence of linkage at that location. Of the 410 sequence differences that we identified, 5 had a frequency <1% in the general population and segregated with diabetes in 3 of the families, including the 2 showing the strongest support for linkage at this location. The 5 mutations were all placed within 100 kb corresponding to the BLK gene. One resulted in an Ala71Thr substitution; the other 4 were noncoding and determined decreased in vitro promoter activity in reporter gene experiments. We found that BLK-a nonreceptor tyrosine-kinase of the src family of proto-oncogenes-is expressed in ␤-cells where it enhances insulin synthesis and secretion in response to glucose by up-regulating transcription factors Pdx1 and Nkx6.1. These actions are greatly attenuated by the Ala71Thr mutation. These findings point to BLK as a previously unrecognized modulator of ␤-cell function, the deficit of which may lead to the development of diabetes.beta cells ͉ genetics ͉ MODY ͉ tyrosine kinase M aturity-onset diabetes of the young or MODY (MIM 606391) is a form of diabetes characterized by an autosomal dominant pattern of inheritance and a relatively young onset (1). The availability of large families with multiple affected members has facilitated studies of this type of diabetes, leading to the identification of 8 distinct MODY genes: HNF4A, encoding hepatocyte nuclear factor 4␣ (2); GCK, encoding glucokinase (3); TCF1, encoding hepatocyte nuclear factor 1␣ (4); IPF1, encoding insulin promoter factor 1 (5); TCF2, encoding hepatocyte nuclear factor 1␤ (6); NEUROD1, encoding neurogenic differentiation 1 (7); KLF11, encoding for kruppel-like factor 11 (8); and CEL, encoding carboxyl-ester lipase (9). However, 15% or more of MODY cases are not accounted for by mutations in these genes, suggesting the existence of as yet undiscovered MODY genes in addition to those identified to date (10, 11). Here we report the identification of mutations at the Blymphocyte kinase (BLK) locus that segregate with diabetes in MODY families unlinked to known MODY genes and have detrimental effects on BLK expression or activity in insulin secreting cells. We further show that BLK is a previously unrecognized modulator of insulin synthesis and secretion that enhances the expression of key ␤-cell transcription factors Pdx-1 and Nkx6.1. ResultsWe previously described a 2.5 Mb region on chromosome 8p23 that segregated with diabetes in extended families with MODY not caused by mutations in known MODY genes (12). To identify causal mutations, we resequenced all transcripts described in this interval as of January 2008 (corresponding to 15 RefSeq genes and 20 EST-derived genes) in 2 diab...

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Section: Discussionmentioning

confidence: 99%

Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction

Borowiec

Liew

Thompson

et al. 2009

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

158

117

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“…Hence, the functional differences of Nkx6.1 and Nkx6.2 seem to be largely determined by the divergent expression pattern of the two genes during embryogenesis. Whereas Nkx6.2 is strongly expressed in Pdx1 + pancreatic progenitors between E8.5 and E10.5, its expression rapidly declines thereafter, and Nkx6.1 becomes the predominantly expressed Nkx6 factor between E11.5 and E13 Pedersen et al, 2005). It is therefore possible that the inability of Nkx6.2 to compensate for Nkx6.1 in beta-cell development is a result of insufficient Nkx6.2 levels in undifferentiated progenitors between E11.5 and E13.…”

Section: Discussionmentioning

confidence: 99%

The transcription factors Nkx6.1 and Nkx6.2 possess equivalent activities in promoting beta-cell fate specification in Pdx1+ pancreatic progenitor cells

2007

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DEVELOPMENT 2491 RESEARCH ARTICLE INTRODUCTIONRecent studies suggest that the most promising approach for the in vitro derivation of insulin-producing pancreatic beta-cells from stem cells is by recapitulating embryonic beta-cell differentiation (D'Amour et al., 2006). The in vitro generation of fully functional beta-cells for transplantation, however, will require further improvement of existing differentiation protocols. Such refinement will require detailed knowledge of the molecular mechanisms that underlie beta-cell differentiation. Lineage-tracing studies in mice have shown that all pancreatic lineages, which include the exocrine and endocrine compartment, arise from a common, proliferative progenitor cell population that is marked by the transcription factor Pdx1 (Gu et al., 2002). Expression of the transcription factor Ngn3 (also known as Neurog3 -Mouse Genome Informatics) further restricts progenitors to five distinct endocrine cell fates: alpha-, beta-, delta-, PP-or epsilon-cells, which produce the hormones glucagon, insulin, somatostatin, pancreatic polypeptide and ghrelin, respectively (Gu et al., 2002;Heller et al., 2005;Prado et al., 2004). Initially, scattered endocrine cells differentiate throughout the organ, but these cells aggregate into so-called islets of Langerhans at the end of gestation (Slack, 1995).In recent years, major progress has been made in our understanding of the molecular pathways that control endocrine differentiation (Jensen, 2004). Much of this knowledge stems from genetic gain-and loss-of-function experiments in mice. Such studies have shown that Ngn3 activity is essential for the differentiation of all endocrine cells and, conversely, that Ngn3 is sufficient to restrict Pdx1-positive (Pdx1 + ) progenitors to an endocrine fate (Apelqvist et al., 1999;Gradwohl et al., 2000;Schwitzgebel et al., 2000). Based on the observation that only select endocrine lineages are affected in null mutant mice for Nkx2.2 (Nkx2-2), NeuroD (Neurod1), Pax4, Arx, Hb9 (also known as Hlxb9 -Mouse Genome Informatics) or Nkx6.1 (Nkx6-1), these transcription factors have been proposed to be downstream effectors of Ngn3 (Collombat et al., 2003;Harrison et al., 1999;Li et al., 1999;Naya et al., 1997;Sander et al., 2000b;Schwitzgebel, 2001;Sosa-Pineda et al., 1997;Sussel et al., 1998;Wilson et al., 2003). Although the loss of Pax4, Arx and NeuroD expression in Ngn3 mutant mice (Collombat et al., 2003;Gradwohl et al., 2000) indeed suggests a function of these genes downstream of Ngn3 in endocrine differentiation, the evidence for Nkx6.1 being downstream of Ngn3 is less clear.Deficiency for Nkx6.1 results in a specific abrogation of beta-cell neogenesis during embryogenesis without affecting cell survival or the development of any other cell type in the pancreas (Sander et al., 2000b). In Nkx6.1 mutant mice, a marked reduction in beta-cell numbers is first apparent at embryonic day (E)14, the time-point at which the first mature beta-cells differentiate. The specific defect in the beta-cell lineage and th...

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“…This homeobox gene was most closely related to the homeobox sequence found in the Nkx gene family members, Nkx6.1 and Nkx6.2, and thus we called it Nkx6.3. This gene has been reported independently by several groups (Alanentalo et al, 2006;Henseleit et al, 2005;Nelson et al, 2005;Pedersen et al, 2005).…”

Section: Identification Of Nkx63 In a Screen Of The Mouse Transcriptmentioning

confidence: 76%

“….3 is more closely related to Drosophila Nk6 than other Nkx gene family members, which raises the possibility that it is the ancestral founder of the vertebrate Nkx6 subfamily (Pedersen et al, 2005). Like its paralogs, Nkx6.3 contains an Engrailed-homology domain that may mediate interaction with transcriptional co-repressors ; however, its physiologic functions have not been fully characterized.…”

Section: Nkx6mentioning

confidence: 99%

“…Like its paralogs, Nkx6.3 contains an Engrailed-homology domain that may mediate interaction with transcriptional co-repressors ; however, its physiologic functions have not been fully characterized. In E12.5 mouse embryos, Nkx6.3 expression is restricted to a subset of differentiating V2 interneurons in the caudal hindbrain that co-labels with Chx10 (Alanentalo et al, 2006) (Pedersen et al, 2005). …”

Section: Nkx6mentioning

confidence: 99%

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Expression and function of Nkx6.3 in vertebrate hindbrain

et al. 2008

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Homeodomain transcription factors serve important functions in organogenesis and tissue differentiation, particularly with respect to the positional identity of individual cells. The Nkx6 subfamily controls tissue differentiation in the developing central nervous system where they function as transcriptional repressor proteins. Recent work indicates that Nkx6.3 is expressed in hindbrain V2 interneurons that co-express Nkx6.1, suggesting the possibility of functional redundancy. Here, we report that Nkx6.3 expression is specific to Chx10 + V2a interneurons but not Gata3 + V2b interneurons of the hindbrain, and that Nkx6.3 expression appears to mark cells of the prospective medullary reticular formation. Molecular analysis of Nkx6.3 null embryonic mouse hindbrain did not reveal detectable defects in progenitor markers, motor neuron or V2 interneuron sub-types. Forced expression of Nkx6.3 and Nkx6.1 promote V2 interneuron differentiation in the developing chick hindbrain. These findings indicate Nkx6.3 function is dispensable for CNS development and lead to the proposal that absence of overt defects is due to functional compensation from a related homeodomain transcription factor. SectionNervous System Development; Regeneration and Aging

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Endodermal expression of Nkx6 genes depends differentially on Pdx1

Cited by 84 publications

References 45 publications

Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction

Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction

The transcription factors Nkx6.1 and Nkx6.2 possess equivalent activities in promoting beta-cell fate specification in Pdx1+ pancreatic progenitor cells

Expression and function of Nkx6.3 in vertebrate hindbrain

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