Postnatal β-Cell Proliferation and Mass Expansion Is Dependent on the Transcription Factor Nkx6.1

Taylor, Brandon; Benthuysen, Jacqueline R.; Sander, Maike

doi:10.2337/db14-0684

Cited by 39 publications

(33 citation statements)

References 26 publications

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“…Nkx6.1 overexpression increases b-cell proliferation, GSIS, and cell survival [7][8][9]. While early studies from another group found no enhancement with Nkx6.1 [43], subsequent studies from the same group support our findings [44,45]. Nkx6.1 overexpression induces expression of the hormone VGF, which enhanced GSIS and increased b-cell survival [9].…”

Section: Discussionsupporting

confidence: 60%

Nkx6.1‐mediated insulin secretion and β‐cell proliferation is dependent on upregulation of c‐Fos

et al. 2016

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Edited by L aszl o NagyUnderstanding the molecular pathways that enhance b-cell proliferation, survival, and insulin secretion may be useful to improve treatments for diabetes. Nkx6.1 induces proliferation through the Nr4a nuclear receptors, and improves insulin secretion and survival through the peptide hormone VGF. Here we demonstrate that Nkx6.1-mediated upregulation of Nr4a1, Nr4a3, and VGF is dependent on c-Fos expression. c-Fos overexpression results in activation of Nkx6.1 responsive genes and increases b-cell proliferation, insulin secretion, and cellular survival. c-Fos knockdown impedes Nkx6.1-mediated b-cell proliferation and insulin secretion. These data demonstrate that c-Fos is critical for Nkx6.1-mediated expansion of functional b-cell mass.

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Section: Discussionsupporting

confidence: 60%

Nkx6.1‐mediated insulin secretion and β‐cell proliferation is dependent on upregulation of c‐Fos

et al. 2016

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“…However, recent studies by Sander and colleagues have shown that Nkx6 . 1 is required for post-natal β-cell expansion [56] and maintenance of β-cell identity [57]. The effects of Nkx6 .…”

Section: Discussionmentioning

confidence: 99%

The Transcription Factor Nfatc2 Regulates β-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets

et al. 2016

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Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the expression of ~40% of the T2D-associated genes is linked to a broad region on mouse chromosome (Chr) 2. As all but 9 of these genes are not physically located on Chr 2, linkage to Chr 2 suggests a genomic factor(s) located on Chr 2 regulates their expression in trans. The transcription factor Nfatc2 is physically located on Chr 2 and its expression demonstrates cis linkage; i.e., its expression maps to itself. When conditioned on the expression of Nfatc2, linkage for the T2D-associated genes was greatly diminished, supporting Nfatc2 as a driver of their expression. Plasma insulin also showed linkage to the same broad region on Chr 2. Overexpression of a constitutively active (ca) form of Nfatc2 induced β-cell proliferation in mouse and human islets, and transcriptionally regulated more than half of the T2D-associated genes. Overexpression of either ca-Nfatc2 or ca-Nfatc1 in mouse islets enhanced insulin secretion, whereas only ca-Nfatc2 was able to promote β-cell proliferation, suggesting distinct molecular pathways mediating insulin secretion vs. β-cell proliferation are regulated by NFAT. Our results suggest that many of the T2D-associated genes are downstream transcriptional targets of NFAT, and may act coordinately in a pathway through which NFAT regulates β-cell proliferation in both mouse and human islets.

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“…In the pancreas, NKX6.1 is exclusively expressed in b-cells and is required for prenatal b-cell development and function and postnatal b-cell expansion (17). In placenta, it remains to be studied whether the epigenetically controlled expression of NKX6.1 is a modulator of nutrient transfer and thus perhaps an indirect modulator of fetal b-cell development, insulin secretion, and fat mass.…”

Section: Discussionmentioning

confidence: 99%

Placental and Cord Blood Methylation of Genes Involved in Energy Homeostasis: Association With Fetal Growth and Neonatal Body Composition

et al. 2016

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Low weight at birth is associated with subsequent susceptibility to diabetes. Epigenetic modulation is among the mechanisms potentially mediating this association. We performed a genome-wide DNA methylation analysis in placentas from term infants born appropriatefor-gestational-age (AGA) or small-for-gestational-age (SGA) to identify new genes related to fetal growth and neonatal body composition. Candidate genes were validated by bisulfite pyrosequencing (30 AGA, 21 SGA) and also analyzed in cord blood. Gene expression analyses were performed by RT-PCR. Neonatal body composition was assessed by dual X-ray absorptiometry at age 2 weeks. The ATG2B, NKX6.1, and SLC13A5 genes (respectively related to autophagy, b-cell development and function, and lipid metabolism) were hypermethylated in placenta and cord blood from SGA newborns, whereas GPR120 (related to free fatty acid regulation) was hypomethylated in placenta and hypermethylated in cord blood. Gene expression levels were opposite to methylation status, and both correlated with birth weight, circulating IGF-I, and total and abdominal fat at age 2 weeks. In conclusion, alterations in methylation and expression of genes involved in the regulation of energy homeostasis were found to relate to fetal growth and neonatal body composition and thus may be among the early mechanisms modulating later susceptibility to diabetes.

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Postnatal β-Cell Proliferation and Mass Expansion Is Dependent on the Transcription Factor Nkx6.1

Cited by 39 publications

References 26 publications

Nkx6.1‐mediated insulin secretion and β‐cell proliferation is dependent on upregulation of c‐Fos

Nkx6.1‐mediated insulin secretion and β‐cell proliferation is dependent on upregulation of c‐Fos

The Transcription Factor Nfatc2 Regulates β-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets

Placental and Cord Blood Methylation of Genes Involved in Energy Homeostasis: Association With Fetal Growth and Neonatal Body Composition

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