Dachshund homologues play a conserved role in islet cell development

Kalousova, Anna; Mavropoulos, Anastasia; Adams, Bruce A.; Nekrep, Nada; Li, Zhongmei; Krauß, Stephan; Stainier, Didier Y. R.; German, Michael S.

doi:10.1016/j.ydbio.2010.09.007

Cited by 27 publications

(40 citation statements)

References 63 publications

(71 reference statements)

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“…Ironically, one of the developmental roles is related to perinatal pancreatic beta cell proliferation, which is associated with DACH1-mediated repression of p27Kip1 (Kalousova et al, 2010). The hypothesis that DACH1 is required for normal insulin secretion was suggested as a mechanism to explain a link between a DACH1 polymorphism and diabetes in a Chinese population (Ma et al, 2014), but replication in additional populations and direct links to beta cell function are needed to substantiate this claim.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

et al. 2016

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SUMMARY Defective insulin signaling in hepatocytes is a key factor in type 2 diabetes. In obesity, activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes suppresses ATF6, which triggers a PERK-ATF4-TRB3 pathway that disrupts insulin signaling. Elucidating how CaMKII suppresses ATF6 is therefore essential to understanding this insulin resistance pathway. We show that CaMKII phosphorylates and blocks nuclear translocation of histone deacetylase 4 (HDAC4). As a result, HDAC4-mediated SUMOylation of the corepressor DACH1 is decreased, which protects DACH1 from proteasomal degradation. DACH1, together with NCOR, represses Atf6 transcription, leading to activation of the PERK-TRB3 pathway and defective insulin signaling. DACH1 is increased in the livers of obese mice and humans, and treatment of obese mice with liver-targeted constitutively-nuclear HDAC4 or DACH1 shRNA increases ATF6, improves hepatocyte insulin signaling, and protects against hyperglycemia and hyperinsulinemia. Thus, DACH1-mediated corepression in hepatocytes emerges as an important link between obesity and insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

et al. 2016

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“…Dac and Ey are evolutionally conserved transcription factors. The mammalian homologs of Dac and Ey have been reported to play important roles in pancreatic islet development (15,25). Furthermore, the Ey homolog Pax6 is required for the normal transcription of pancreatic hormone genes, including Insulin and Glucagon (15,16).…”

Section: Mammalian Dac Homolog Dach Facilitates Pax6 Function On Isletmentioning

confidence: 99%

“…Furthermore, the Ey homolog Pax6 is required for the normal transcription of pancreatic hormone genes, including Insulin and Glucagon (15,16). Although the Dac homolog Dach1 is expressed in both pancreatic α-and β-cells throughout development (25), the contribution of Dach1/ 2 toward islet hormone gene expression remains unknown. To determine whether the synergistic action of Dac and Ey is conserved in mammals, we analyzed reporter gene expression using the Insulin and Glucagon promoters.…”

Section: Mammalian Dac Homolog Dach Facilitates Pax6 Function On Isletmentioning

confidence: 99%

Conserved role for the Dachshund protein with Drosophila Pax6 homolog Eyeless in insulin expression

Okamoto¹,

Nishimori²,

Nishimura³

2012

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

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Members of the insulin family peptides have conserved roles in the regulation of growth and metabolism in a wide variety of metazoans. The Drosophila genome encodes seven insulin-like peptide genes, dilp1-7, and the most prominent dilps (dilp2, dilp3, and dilp5) are expressed in brain neurosecretory cells known as "insulin-producing cells" (IPCs). Although these dilps are expressed in the same cells, the expression of each dilp is regulated independently. However, the molecular mechanisms that regulate the expression of individual dilps in the IPCs remain largely unknown. Here, we show that Dachshund (Dac), which is a highly conserved nuclear protein, is a critical transcription factor that specifically regulates dilp5 expression. Dac was strongly expressed in IPCs throughout development. dac loss-of-function analyses revealed a severely reduced dilp5 expression level in young larvae. Dac interacted physically with the Drosophila Pax6 homolog Eyeless (Ey), and these proteins synergistically promoted dilp5 expression. In addition, the mammalian homolog of Dac, Dach1/2, facilitated the promoting action of Pax6 on the expression of islet hormone genes in cultured mammalian cells. These observations indicate the conserved role of Dac/Dach in controlling insulin expression in conjunction with Ey/Pax6.

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“…DACH1 is a helix-turn-helix transcription factor related to the Sno/Ski family of corepressors and was initially discovered for its role in cell specification and organ size control in Drosophila (Mardon et al 1994). In mammals, it plays a role in determining pancreas size by supporting progenitor cell proliferation through the suppression of the cyclin-dependent kinase inhibitor P27KIP1 (Kalousova et al 2010). DACH1 also inhibits cell cycle progression in tumor cell lines, and its suppression has been associated with poor prognosis in human breast cancer (Popov et al 2010).…”

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confidence: 99%

DACH1 stimulates shear stress-guided endothelial cell migration and coronary artery growth through the CXCL12–CXCR4 signaling axis

et al. 2017

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Sufficient blood flow to tissues relies on arterial blood vessels, but the mechanisms regulating their development are poorly understood. Many arteries, including coronary arteries of the heart, form through remodeling of an immature vascular plexus in a process triggered and shaped by blood flow. However, little is known about how cues from fluid shear stress are translated into responses that pattern artery development. Here, we show that mice lacking endothelial Dach1 had small coronary arteries, decreased endothelial cell polarization, and reduced expression of the chemokine Cxcl12. Under shear stress in culture, Dach1 overexpression stimulated endothelial cell polarization and migration against flow, which was reversed upon CXCL12/CXCR4 inhibition. In vivo, DACH1 was expressed during early arteriogenesis but was down in mature arteries. Mature artery-type shear stress (high, uniform laminar) specifically down-regulated DACH1, while the remodeling artery-type flow (low, variable) maintained DACH1 expression. Together, our data support a model in which DACH1 stimulates coronary artery growth by activating Cxcl12 expression and endothelial cell migration against blood flow into developing arteries. This activity is suppressed once arteries reach a mature morphology and acquire high, laminar flow that down-regulates DACH1. Thus, we identified a mechanism by which blood flow quality balances artery growth and maturation.

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Dachshund homologues play a conserved role in islet cell development

Cited by 27 publications

References 63 publications

Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

Conserved role for the Dachshund protein with Drosophila Pax6 homolog Eyeless in insulin expression

DACH1 stimulates shear stress-guided endothelial cell migration and coronary artery growth through the CXCL12–CXCR4 signaling axis

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