Alternative titles; symbols
HGNC Approved Gene Symbol: INSM1
Cytogenetic location: 20p11.23 Genomic coordinates (GRCh38): 20:20,368,104-20,370,949 (from NCBI)
By differential screening of human insulinoma and glucagonoma cDNA libraries, Goto et al. (1992) cloned INSM1, which they called IA1. The 3-prime UTR has 2 polyadenylation signals. The deduced 510-amino acid protein has a calculated molecular mass of 52.9 kD. IA1 has an N-terminal domain with 4 classical prohormone dibasic conversion sites and an amidation signal sequence. The C-terminal domain contains 5 putative C2H2-type zinc finger DNA-binding motifs. Northern blot analysis detected a 3.0-kb transcript in all human and rodent insulinomas examined, but not in any normal tissues. IA1 was also expressed in several tumor cell lines of neuroendocrine origin.
Lan et al. (1994) cloned and sequenced the entire IA1 gene and its 5-prime upstream region from a human liver genomic library. In vitro translation studies showed that IA1 cDNA and IA1 genomic DNA yielded identical protein products of approximately 61 kD.
Xie et al. (2002) cloned mouse Insm1 from a beta-cell cDNA library. The deduced 521-amino acid protein is 86% identical to human INSM1, and both proteins contain proline-rich regions and multiple zinc finger DNA-binding motifs. Northern blot analysis revealed that mouse Insm1 expression began at embryonic day 10.5, decreased after day 13.5, was barely detectable at day 18.5. In mouse brain, Insm1 was strongly expressed for 2 weeks after birth, but it showed little to no expression thereafter. Fluorescence-tagged Insm1 was expressed exclusively in nuclei of transfected cells.
By in situ hybridization and immunohistologic analysis, Gierl et al. (2006) found widespread expression of mouse Insm1 in the developing central and peripheral nervous system and pancreas. It was also present in adult pancreatic islets.
Clinical studies by Lan et al. (1994) demonstrated that IA1 is a sensitive marker for neuroendocrine differentiation of human lung tumors.
By yeast 2-hybrid analysis, in vitro pull-down experiments, nuclear colocalization, and coimmunoprecipitation assays, Xie et al. (2002) showed the mouse Insm1 interacted with Cap (SORBS1; 605264).
Using a chromatin immunoprecipitation assay, Liu et al. (2006) found that INSM1 bound the promoter region of mouse Neurod1 (601724) following transfection in HEK293 cells. Yeast 2-hybrid analysis of a human fetal brain cDNA library showed that cyclin D1 (CCND1; 168461) bound INSM1, and in vitro and in vivo pull-down assays confirmed the interaction. Coimmunoprecipitation assays of mammalian cells revealed that INSM1 interacted with HDAC1 (601241) and HDAC3 (605166) and that the interaction was mediated through cyclin D1. Cyclin D1 cooperated with INSM1 to suppress Neurod1 promoter activity, and overexpression of cyclin D1 and HDAC3 significantly enhanced the transcriptional repression activity of INSM1 on the Neurod1 promoter. A chromatin immunoprecipitation assay showed that HDAC3 occupied the same region of the Neurod1 promoter by forming a transcription complex with INSM1. Liu et al. (2006) concluded that INSM1 recruits cyclin D1 and HDACs, which confer transcriptional repressor activity.
In mice, Wiwatpanit et al. (2018) demonstrated that Insm1, which encodes a zinc finger protein that is transiently expressed in nascent outer hair cells, consolidates their fate by preventing trans-differentiation into inner hair cells. In the absence of Insm1, many hair cells that were born as outer hair cells switched fates to become mature inner hair cells. To identify the genetic mechanisms by which Insm1 operates, Wiwatpanit et al. (2018) compared the transcriptomes of immature inner hair cells and outer hair cells, and of outer hair cells with and without Insm1. In outer hair cells that lacked Insm1, a set of genes was upregulated, most of which are normally preferentially expressed by inner hair cells. The homeotic cell transformation of outer hair cells without Insm1 into inner hair cells revealed a mechanism by which these neighboring mechanosensory cells begin to differ: Insm1 represses a core set of early inner hair cell-enriched genes in embryonic outer hair cells and makes them unresponsive to an inner hair cell-inducing gradient, so that they proceed to mature as outer hair cells. Without Insm1, some of the outer hair cells in which these few inner hair cell-enriched transcripts were upregulated trans-differentiated into inner hair cells, identifying candidate genes for inner hair cell-specific differentiation.
Lan et al. (1994) determined that the IA1 gene is intronless. Examination of the 5-prime upstream region demonstrated several tissue-specific regulatory elements. Xie et al. (2002) determined that the mouse Insm1 gene is also intronless.
By fluorescence in situ hybridization, Lan et al. (1994) mapped the INSM1 gene to chromosome 20p11.2. Xie et al. (2002) mapped the mouse Insm1 gene to chromosome 2.
Gierl et al. (2006) found that homozygous Insm1-null mouse embryos were normal in size and well developed until embryonic day 12.5. However, after day 12.5, Insm1-null embryos were recovered at lower than the expected frequency, and at birth, Insm1-null mice appeared unable to breathe and died. Creating Insm1-null mice on a mixed genetic background reduced the embryonic lethality. Endocrine precursors formed in the pancreas of Insm1-null mice, but only few insulin (INS; 176730)-positive beta cells were generated. Instead, endocrine precursors accumulated and expressed none of the pancreatic hormones. A similar change was observed in the developing intestine, where endocrine precursors formed but did not differentiate correctly. Accumulation of proteins that participate in secretion and vesicle transport is a hallmark of endocrine cell differentiation, and Insm1-null mice showed reduced expression of genes encoding such proteins. Gierl et al. (2006) concluded that INSM1 controls a gene expression program for hormones and proteins of the secretory machinery.
Gierl, M. S., Karoulias, N., Wende, H., Strehle, M., Birchmeier, C. The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells. Genes Dev. 20: 2465-2478, 2006. [PubMed: 16951258] [Full Text: https://doi.org/10.1101/gad.381806]
Goto, Y., De Silva, M. G., Toscani, A., Prabhakar, B. S., Notkins, A. L., Lan, M. S. A novel human insulinoma-associated cDNA, IA-1, encodes a protein with 'zinc-finger' DNA-binding motifs. J. Biol. Chem. 267: 15252-15257, 1992. [PubMed: 1634555]
Lan, M. S., Li, Q., Lu, J., Modi, W. S., Notkins, A. L. Genomic organization, 5-prime-upstream sequence, and chromosomal localization of an insulinoma-associated intronless gene, IA-1. J. Biol. Chem. 269: 14170-14174, 1994. [PubMed: 8188699]
Liu, W.-D., Wang, H.-W., Muguira, M., Breslin, M. B., Lan, M. S. INSM1 functions as a transcriptional repressor of the neuroD/beta-2 gene through the recruitment of cyclin D1 and histone deacetylases. Biochem. J. 397: 169-177, 2006. [PubMed: 16569215] [Full Text: https://doi.org/10.1042/BJ20051669]
Wiwatpanit, T., Lorenzen, S. M., Cantu, J. A., Foo, C. Z., Hogan, A. K., Marquez, F., Clancy, J. C., Schipma, M. J., Cheatham, M. A., Duggan, A., Garcia-Anoveros, J. Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1. Nature 563: 691-695, 2018. Note: Erratum: Nature 565: E2, 2019. Electronic Article. [PubMed: 30305733] [Full Text: https://doi.org/10.1038/s41586-018-0570-8]
Xie, J., Cai, T., Zhang, H., Lan, M. S., Notkins, A. L. The zinc-finger transcription factor INSM1 is expressed during embryo development and interacts with the Cbl-associated protein. Genomics 80: 54-61, 2002. [PubMed: 12079283] [Full Text: https://doi.org/10.1006/geno.2002.6800]