Transient Neonatal Diabetes Mellitus Gene Zac1 Impairs Insulin Secretion in Mice through Rasgrf1

Abstract

The biallelic expression of the imprinted gene ZAC1/PLAGL1 underlies ϳ60% of all cases of transient neonatal diabetes mellitus (TNDM) that present with low perinatal insulin secretion. Molecular targets of ZAC1 misexpression in pancreatic ␤ cells are unknown. Here, we identified the guanine nucleotide exchange factor Rasgrf1 as a direct Zac1/Plagl1 target gene in murine ␤ cells. Doubling Zac1 expression reduced Rasgrf1 expression, the stimulus-induced activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, and, ultimately, insulin secretion. Normalizing Rasgrf1 expression reversed this phenotype. Moreover, the transplantation of Zac1-overexpressing ␤ cells failed to reinstate euglycemia in experimental diabetic mice. In contrast, Zac1 expression did not interfere with the signaling of the glucagon-like peptide 1 receptor (GLP-1R), and the GLP-1 analog liraglutide improved hyperglycemia in transplanted experimental diabetic mice. This study unravels a mechanism contributing to insufficient perinatal insulin secretion in TNDM and raises new prospects for therapy.

Zac1 Regulates Cell Cycle Arrest in Neuronal Progenitors via Tcf4

“…However, the mechanisms underlying such connectivity remained incompletely understood. In this regard, we recently showed that Zac1 directly represses the paternally imprinted gene Rasgrf1, leading to an inhibition of glucose-stimulated insulin secretion in pancreatic ␤ cells (23). Here, we show that imprinted genes can also be connected via regulatory networks that involve proneural factors such as Tcf4.…”

“…The mouse C17.2 NSC line was cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum (FCS) (both from Life Technologies GmbH, Darmstadt, Germany). Tetracycline (Tc)-regulated Zac1 expression in C17.2 cells was established, and proliferation was measured as described previously (21,23). The mouse embryonic stem cell (ESC) line 46C was grown, and neuronal differentiation was performed as reported previously (25).…”

“…Kip2 (sc-8298; Santa Cruz), and Zac1 (guinea pig polyclonal) (23,24). Nuclei were stained with 2-(4-amidinophenyl)-6-indolecarbamidine-dihydrochloride (DAPI).…”

“…Direct Zac1 target genes identified so far include the G-protein-coupled receptor PacI (pituitary adenylate-activating receptor I) gene (18)(19)(20), the nuclear receptor gene Ppar␥1 (peroxisome proliferatoractivated receptor gene) (21), the cyclin-dependent kinase inhibitor gene p21 Waf1/Cip1 (22), and the exchange factor gene Rasgrf1 (RAS protein-specific guanine nucleotide-releasing factor 1 gene) (23), all of which share a role in the regulation of apoptosis, cell cycle arrest, and differentiation across different tissues and stages of development. Moreover, we recently found that Zac1 expression prevents precocious astroglial differentiation by restraining Jak/Stat3 signaling in embryonic and adult neural stem cells (NSCs) through transcriptional induction of Socs3 (24).…”

Транзиторный неонатальный сахарный диабет, ассоциированный с нарушением импринтинга хромосомы 6q24 Часть 4. Дифференциальная диагностика и лечение

“…Anke Hoffmann и Dietmar Spengler [31] в экспе-рименте показали, что при лечении гипергликемии, вызванной гиперэкспрессией гена Zac1, могут быть эффективными глюкагон и агонист рецепторов глю-кагон-подобного протеина 1 (GLP-1R) лираглутид.…”