The SNAG Domain of Insm1 Regulates Pancreatic Endocrine Cell Differentiation and Represses ß- to δ-Cell Transdifferentiation.

The allocation and specification of pancreatic endocrine lineages are tightly regulated by transcription factors. Disturbances in differentiation of these lineages contribute to the development of various metabolic diseases, including diabetes. The insulinoma-associated protein 1 (Insm1), which encodes a protein containing one SNAG domain and five zinc fingers, plays essential roles in pancreatic endocrine cell differentiation and in mature ß-cell function. In the current study, we compared the differentiation of pancreatic endocrine cells between Insm1 null and Insm1 SNAG domain mutants (Insm1delSNAG) to explore the specific function of the SNAG domain of Insm1. We show that the δ-cell number is increased in Insm1delSNAG but not in Insm1 null mutants as compared with the control mice. We also show a less severe reduction of the ß-cell number in Insm1delSNAG as that in Insm1 null mutants. In addition, similar deficits are observed in α-, PP, and ε-cells in Insm1delSNAG and Insm1 null mutants. We further identified that the increased δ-cell number is due to ß- to δ-cell transdifferentiation. Mechanistically, the SNAG domain of Insm1 interacts with Lsd1, the demethylase of H3K4me1/2. Mutation in the SNAG domain of Insm1 results in impaired recruitment of Lsd1 and increased H3K4me1/2 levels at hematopoietically expressed homeobox (Hhex) loci that are bound by Insm1, thereby promoting the transcriptional activity of the δ-cell-specific gene Hhex Our study has identified a novel function of the SNAG domain of Insm1 in the regulation of pancreatic endocrine cell differentiation, particularly in the repression of ß- to δ-cell transdifferentiation.

Semaphorin and neuropilin expression during early morphogenesis of Xenopus laevis.

Semaphorins are major regulators of morphogenesis and are involved in a variety of processes ranging from the guidance of cell migration to the development of cancer. Since semaphorins were first characterized as repulsive neuronal guidance cues, their expression has been best documented in the nervous system. However, broader studies are lacking. Here, we describe the expression of 13 members of the semaphorin family and two neuropilin receptors during early Xenopus laevis development. No particular expression pattern defines any of the semaphorin classes, but many are dynamically expressed in distinct areas undergoing morphogenetic cell movements like the developing mesoderm and the migrating neural crest. Furthermore, the complementary expression patterns of Sema3A/Nrp1 and Sema3F/Nrp2 are maintained across hundreds of millions of years, possibly indicating a conserved role in the guidance of migrating neural crest cells.