Abstract
BackgroundNeurogenin3 (Ngn3) and neurogenic differentiation 1 (NeuroD1), two crucial transcriptional factors involved in human diabetes (OMIM: 601724) and islet development, have been previously found to directly target to the E-boxes of the insulinoma-associated 2 (Insm2) gene promoter, thereby activating the expression of Insm2 in insulin-secretion cells. However, little is known about the function of Insm2 in pancreatic islets and glucose metabolisms.MethodsHomozygous Insm2−/− mice were generated by using the CRISPR-Cas9 method. Glucose-stimulated insulin secretion and islet morphology were analyzed by ELISA and immunostainings. Expression levels of Insm2-associated molecules were measured using quantitative RT-PCR and Western blots.ResultsFasting blood glucose levels of Insm2−/− mice were higher than wild-type counterparts. Insm2−/− mice also showed reduction in glucose tolerance and insulin/C-peptide levels when compared to the wild-type mice. RT-PCR and Western blot analysis revealed that expression of Insm1 was significantly increased in Insm2−/− mice, suggesting a compensatory response of the homolog gene Insm1. Similarly, transcriptional levels of Ngn3 and NeuroD1 were also increased in Insm2−/− mice. Moreover, Insm2−/− female mice showed a significantly decreased reproductive capacity.ConclusionsOur findings suggest that Insm2 is important in glucose-stimulated insulin secretion and is involved in the development pathway of neuroendocrine tissues which are regulated by the transcription factors Ngn3, NeuroD1 and Insm1.
Highlights
Neurogenin3 (Ngn3) and neurogenic differentiation 1 (NeuroD1), two crucial transcriptional factors involved in human diabetes (OMIM: 601724) and islet development, have been previously found to directly target to the E-boxes of the insulinoma-associated 2 (Insm2) gene promoter, thereby activating the expression of Insm2 in insu‐ lin-secretion cells
Our findings suggest that Insm2 is important in glucose-stimulated insulin secretion and is involved in the development pathway of neuroendocrine tissues which are regulated by the transcription factors Ngn3, NeuroD1 and Insm1
Wild-type (Insm2+/+), heterozygous (Insm2+/−), and homozygous (Insm2−/−) mice were identified by tail DNA PCR and Sanger sequencing with the allele-specific primers (Fig. 1b)
Summary
Neurogenin (Ngn3) and neurogenic differentiation 1 (NeuroD1), two crucial transcriptional factors involved in human diabetes (OMIM: 601724) and islet development, have been previously found to directly target to the E-boxes of the insulinoma-associated 2 (Insm2) gene promoter, thereby activating the expression of Insm in insu‐ lin-secretion cells. Insm2−/− mice showed reduction in glucose tolerance and insulin/C-peptide levels when compared to the wild-type mice. RT-PCR and Western blot analysis revealed that expression of Insm was significantly increased in Insm2−/− mice, suggesting a compensatory response of the homolog gene Insm. Transcriptional levels of Ngn and NeuroD1 were increased in Insm2−/− mice. NeuroD1, Previously we reported the isolation of two homologous genes, INSM1 (a.k.a. IA-1) [7] and INSM2 (INSM transcriptional repressor 2; a.k.a. IA-6) [8], from human pancreatic islet cells. Two additional genes, named PTPRN and PTPRN2 (a.k.a., IA-2 and IA-2beta), were isolated from human islet cells, which have been
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