NeuroD1 in the endocrine pancreas: Localization and dual function as an activator and repressor

Itkin-Ansari, Pamela; Marcora, Edoardo; Geron, Ifat; Tyrberg, Björn; Demeterco, Carla; Hao, Ergeng; Padilla, Christopher M.; Ratineau, Christelle; Leiter, Andrew B.; Lee, J.E.; Levine, Fred

doi:10.1002/dvdy.20443

Cited by 58 publications

(44 citation statements)

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“…By e16.5, ␤-galactosidase staining could be detected in each of the hormone-producing cell populations, with the exception of somatostatin-producing ␦ cells (Fig. 1, D-P), similar to the findings of ItkinAnsari et al (19). Interestingly, many of the insulin, glucagon, and PP cells at e16.5 did not co-express ␤-galactosidase, which may reflect the maturation state of the cell.…”

Section: Neurod1 Gene Expression Is Decreased In Nkx22 Null Micesupporting

confidence: 86%

“…In the developing pancreas, NeuroD1 is detected as early as e9.5 in the early glucagon-producing populations (14). By birth, NeuroD1 is predominantly localized to the insulin-producing ␤ cell population, although expression is maintained in a subset of glucagon-producing cells in embryonic pancreata and in perinatal immature islets (14,19). Despite the early expression of NeuroD1 in the developing pancreas, NeuroD1 null mice do not exhibit phenotypes until late gestation.…”

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confidence: 99%

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Cooperative Transcriptional Regulation of the Essential Pancreatic Islet Gene NeuroD1 (Beta2) by Nkx2.2 and Neurogenin 3

Anderson

Torres

Solomon

et al. 2009

Journal of Biological Chemistry

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Nkx2.2 and NeuroD1 are two critical regulators of pancreatic ␤ cell development. Nkx2.2 is a homeodomain transcription factor that is essential for islet cell type specification and mature ␤ cell function. NeuroD1 is a basic helix-loop-helix transcription factor that is critical for islet ␤ cell maturation and maintenance. Although both proteins influence ␤ cell development directly downstream of the endocrine progenitor factor, neurogenin3 (Ngn3), a connection between the two proteins in the regulation of ␤ cell fate and function has yet to be established. In this study, we demonstrate that Nkx2.2 transcriptional activity is required to facilitate the activation of NeuroD1 by Ngn3. Furthermore, Nkx2.2 is necessary to maintain high levels of NeuroD1 expression in developing mouse and zebrafish islets and in mature ␤ cells. Interestingly, Nkx2.2 regulates NeuroD1 through two independent promoter elements, one that is bound and activated directly by Nkx2.2 and one that appears to be regulated by Nkx2.2 through an indirect mechanism. Together, these findings suggest that Nkx2.2 coordinately activates NeuroD1 with Ngn3 within the endocrine progenitor cell and also plays a role in the maintenance of NeuroD1 expression to regulate ␤ cell function in the mature islet. Collectively, these findings further define the conserved regulatory networks involved in islet ␤ cell formation and function.The pancreas is an intricate organ composed of exocrine tissue that secretes digestive enzymes into pancreatic ducts, and the endocrine islets of Langerhans that produce the metabolic hormones insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin. The different pancreatic cell lineages arise during the critical developmental events referred to as the primary and secondary transitions (Ref. 1; reviewed in Ref. 2). The primary transition occurs between embryonic day (e) 8.5 and e11.5 2 and encompasses the initial patterning and specification of the pancreatic endoderm, which originates from the foregut. The secondary transition is the critical stage between e12.5 and e15.5 when endocrine and exocrine progenitors expand and a large second wave of differentiation is initiated. The secondary transition also marks an increase in the expression and/or relocalization of a number of transcription factors that are important in pancreatic development, including Pdx1, Ptf1a, Ngn3, Nkx2.2, NeuroD1, Pax4, Pax6, and Nkx6.1 (reviewed in Ref. 3). A large number of studies of these transcription factors have yielded a timeline of gene expression and determined which cell lineages are regulated by each transcription factor (2-7). Notably, temporal and spatial changes in many of the transcription factor expression profiles can re-program a progenitor or precursor cell to alter, prevent, or initiate endocrine differentiation (3, 8 -12). The cumulative findings of these studies have illustrated that the regulation of islet cell differentiation depends on complex relationships between the transcriptional regulatory cascades. These regulato...

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Section: Neurod1 Gene Expression Is Decreased In Nkx22 Null Micesupporting

confidence: 86%

mentioning

confidence: 99%

Cooperative Transcriptional Regulation of the Essential Pancreatic Islet Gene NeuroD1 (Beta2) by Nkx2.2 and Neurogenin 3

Anderson

Torres

Solomon

et al. 2009

Journal of Biological Chemistry

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“…It has been postulated that the involvement of Neuro D1 in promoting cell cycle exit inducing pancreatic progenitor cells to differentiate. 45 Thus, HOXD13 deregulation in brain, prostate and pancreatic cancers appears to be related to the neurogenic and neuroendocrine characteristics of this genomic landscape.…”

Section: Discussionmentioning

confidence: 99%

HOX D13 expression across 79 tumor tissue types

Cantile

Franco

Tschan

et al. 2009

Intl Journal of Cancer

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HOX genes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Locus D HOX genes play an important role in limb generation and mesenchymal condensation. Dysregulated HOXD13 expression has been detected in breast cancer, melanoma, cervical cancer and astrocytomas. We have investigated the epidemiology of HOXD13 expression in human tissues and its potential deregulation in the carcinogenesis of specific tumors. HOXD13 homeoprotein expression has been detected using microarray technology comprising more than 4,000 normal and neoplastic tissue samples including 79 different tumor categories. Validation of HOXD13 expression has been performed, at mRNA level, for selected tumor types. Significant differences are detectable between specific normal tissues and corresponding tumor types with the majority of cancers showing an increase in HOXD13 expression (16.1% normal vs. 57.7% cancers). In contrast, pancreas and stomach tumor subtypes display the opposite trend. Interestingly, detection of the HOXD13 homeoprotein in pancreas-tissue microarrays shows that its negative expression has a significant and adverse effect on the prognosis of patients with pancreatic cancer independent of the T or N stage at the time of diagnosis. Our study provides, for the first time, an overview of a HOX protein expression in a large series of normal and neoplastic tissue types, identifies pancreatic cancer as one of the most affected by the HOXD13 hoemoprotein and underlines the way homeoproteins can be associated to human cancerogenesis. ' UICCKey words: HOXD13; HOX and multitumor tissue microarray; HOXD13 and pancreas Class I Homeobox genes (Hox, mice; HOX, human) are transcription factors mostly involved in embryonic development. 1 They display an unique genomic network organization: 4 compact chromosomal loci (HOXA at 7p15.3, HOXB at 17q21.3, HOXC at 12q13.3 and HOXD at 2q31 2 ) where 39 sequence corresponding genes can be aligned with each other into 13 antero-posterior paralogous groups. The HOX gene network, the most repeat-poor regions in the human genome, 3 is also expressed in normal adult human organs. 4 HOX genes appear to regulate phenotype cell identity, 5,6 cell differentiation 7,8 and control primary cellular processes, as proven by the description of congenital, 9 somatic 10 and metabolic 11 diseases involving these genes. Furthermore, besides the already established role of the HOX network in hematopoiesis and leukemogenesis, 12 HOX genes are implicated in the neoplastic alterations of human solid tissues and organs such as kidney, colon, lung, skin, bladder, liver, breast and prostate. 13,14 New crucial functions have recently been ascribed to HOX genes and homeoproteins mostly related to their interaction with miRNAs and ncRNAs to guarantee transcription and export of specific mRNAs. 15,16 Locus D HOX genes are localized on chromosome 2q31-32 and play a role, with its posterior paralogous genes, in limb and digit generation during embryonic development 1...

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“…6C). As for NeuroD, it is expressed in the murine Ngn3 pancreatic precursors as well as in the mature hormone-expressing cells (Huang et al, 2000;Itkin-Ansari et al, 2005;Naya et al, 1997).…”

Section: Research Articlementioning

confidence: 99%

Rfx6 is an Ngn3-dependent winged helix transcription factor required for pancreatic islet cell development

et al. 2010

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SUMMARYThe transcription factor neurogenin 3 (Neurog3 or Ngn3) controls islet cell fate specification in multipotent pancreatic progenitor cells in the mouse embryo. However, our knowledge of the genetic programs implemented by Ngn3, which control generic and islet subtype-specific properties, is still fragmentary. Gene expression profiling in isolated Ngn3-positive progenitor cells resulted in the identification of the uncharacterized winged helix transcription factor Rfx6. Rfx6 is initially expressed broadly in the gut endoderm, notably in Pdx1-positive cells in the developing pancreatic buds, and then becomes progressively restricted to the endocrine lineage, suggesting a dual function in both endoderm development and islet cell differentiation. Rfx6 is found in postmitotic islet progenitor cells in the embryo and is maintained in all developing and adult islet cell types. Rfx6 is dependent on Ngn3 and acts upstream of or in parallel with NeuroD, Pax4 and Arx transcription factors during islet cell differentiation. In zebrafish, the Rfx6 ortholog is similarly found in progenitors and hormone expressing cells of the islet lineage. Loss-of-function studies in zebrafish revealed that rfx6 is required for the differentiation of glucagon-, ghrelin-and somatostatin-expressing cells, which, in the absence of rfx6, are blocked at the progenitor stage. By contrast, beta cells, whose number is only slightly reduced, were no longer clustered in a compact islet. These data unveil Rfx6 as a novel regulator of islet cell development.

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NeuroD1 in the endocrine pancreas: Localization and dual function as an activator and repressor

Cited by 58 publications

References 50 publications

Cooperative Transcriptional Regulation of the Essential Pancreatic Islet Gene NeuroD1 (Beta2) by Nkx2.2 and Neurogenin 3

Cooperative Transcriptional Regulation of the Essential Pancreatic Islet Gene NeuroD1 (Beta2) by Nkx2.2 and Neurogenin 3

HOX D13 expression across 79 tumor tissue types

Rfx6 is an Ngn3-dependent winged helix transcription factor required for pancreatic islet cell development

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