The Zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic β cells and intestinal endocrine cells

Gierl, Mathias S.; Karoulias, Nikolaos; Wende, Hagen; Strehle, Michael; Birchmeier, Carmen

doi:10.1101/gad.381806

Cited by 195 publications

(234 citation statements)

References 55 publications

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“…Such deficiencies are also observed in Insulinoma-associated antigen 1 (Insm1), Regulatory X-box binding 6 (Rfx6), and Islet1 (Isl1) mutants. Loss of Insm1 or Rfx6 arrests the differentiation of endocrine precursors towards hormone-expressing cells (Gierl et al, 2006;Mellitzer et al, 2006;Soyer et al, 2010;Smith et al, 2010). A phenotype similar to Rfx6 mutant mice has also been reported in human infants carrying mutation in the Rfx6 gene, who have an autosomal recessive syndrome of neonatal diabetes, Mitchell-Riley syndrome (Smith et al, 2010).…”

Section: Class I: General Endocrine Precursor Differentiation Factorsmentioning

confidence: 81%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

528

594

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Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

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Section: Class I: General Endocrine Precursor Differentiation Factorsmentioning

confidence: 81%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

528

594

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“…The INSM1 transcription factor has emerged as an important regulator for pancreatic endocrine cell differentiation (4,5). Extensive biochemical studies have revealed the DNA consensus binding sequence, transcriptional repressor activity, downstream target genes, upstream regulatory protein of INSM1, and its restricted expression pattern (1-3, 9, 14, 15).…”

Section: Discussionmentioning

confidence: 99%

Zinc Finger Transcription Factor INSM1 Interrupts Cyclin D1 and CDK4 Binding and Induces Cell Cycle Arrest

Zhang

Liu

Saunée

et al. 2009

Journal of Biological Chemistry

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INSM12 (formerly IA-1) is a zinc finger transcription factor originally isolated from a human insulinoma subtraction library (1). Functional analysis of INSM1 revealed that multiple downstream target genes and upstream regulatory proteins of the INSM1 gene are closely associated with pancreatic endocrine cell differentiation (2-4). Global deletion of the INSM1 gene was embryonic lethal and resulted in abnormal ␤-cell development (5) as well as impaired sympatho-adrenal lineage development (6). The expression patterns of INSM1 in both humans and rodents are restricted to the fetal neuroendocrine system and silenced in adult tissues (1, 7-9). However, the INSM1 gene is reactivated in tumors of neuroendocrine origin, suggesting that de-differentiation events occur in neuroendocrine tumors that mimic normal embryonic development. Embryonic development requires the generation of cells in appropriate numbers and the timely acquisition of specialized cell functions (10). Specialization occurs gradually over multiple rounds of cell division, with the end point being a nondividing terminally differentiated cell. Usually, cell fate determination is controlled in part by external signals and/or differentiation factors that govern cells to either enter or exit the cell cycle. Our previous study revealed a direct interaction between INSM1 and cyclin D1 (11). Therefore, we hypothesize that INSM1 could not only function as a transcription factor in regulating its downstream target genes but also plays an important role in switching between cellular proliferation and differentiation pathways.In the present study, the cyclin box of cyclin D1 was identified to be essential for INSM1 binding. Conversely, a proline-rich N-terminal region (amino acids 43-58) in INSM1 facilitates binding to cyclin D1. The cyclin box is known to be the main binding site for cyclin-dependent kinase 4 (CDK4) (12). Competitive immunoprecipitation of cyclin D1 with INSM1 or CDK4 demonstrated that INSM1 could interrupt CDK4 binding, subsequently induced Rb protein hypophosphorylation, and cell cycle arrest. We employed an INSM1 Tet-on system in Cos-7 and Panc-1 cells. Induction of INSM1 in these cells results in cell cycle arrest and inhibition of cellular proliferation. EXPERIMENTAL PROCEDURESCell Lines and Chemicals-An African green monkey kidney cell line (Cos-7) and a human pancreatic carcinoma cell line (Panc-1) were obtained from ATCC and maintained according to the ATCC recommendation. ␤TC-1 cells were kindly provided by Dr. E. H. Leiter (Jackson Laboratory, Bar Harbor, ME). Antibodies to CDK4 (C-22), cyclin D1, phospho-Rb 780 , and Rb were purchased from BD Biosciences (Palo Alto, CA). Anti-GFP was purchased from Clontech (Palo Alto, CA). A mouse anti-INSM1 monoclonal antibody (6-1-1) was generated against the C-terminal peptide of the INSM1 protein. Anti-FLAG and anti-actin antibodies were purchased from Sigma. Anti-hemagglutinin antibody was obtained from BIOSOURCE (Camarillo, CA). * This work was supported, in whole or in part, by National Insti...

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“…A predicted binding site for MyT1, a known pancreatic transcription factor (50), was identified within the fp3 region. Putative binding sites for IA1 and HNF4, two additional well characterized pancreatic regulatory factors (51)(52)(53), are coincident with the fp4 region, as were possible binding sites for two generally expressed regulatory factors, Sp1 and GABP. The fp5 region also contained a second Sp1 site.…”

Section: Dna Footprint Analysis Of the Proximal Site 2-and Site 3-conmentioning

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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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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The Zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic β cells and intestinal endocrine cells

Cited by 195 publications

References 55 publications

Pancreas organogenesis: From bud to plexus to gland

Pancreas organogenesis: From bud to plexus to gland

Zinc Finger Transcription Factor INSM1 Interrupts Cyclin D1 and CDK4 Binding and Induces Cell Cycle Arrest

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

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