The pancreas is a complex organ that contains ductal, exocrine and endocrine tissues. Here (), Kristin Artinger, Lori Sussel and co-workers identify a role for Tm4sf4, a tetraspanin-like protein, during pancreatic endocrine differentiation. Tm4sf4 expression in mice is downregulated by the transcription factor Nkx2.2, which is known to be essential for islet cell differentiation. The researchers show that, in mice, Tm4sf4 is expressed in the pancreatic ductal epithelial compartment and is abundant in islet progenitor cells. Pancreatic tm4sf4 expression and its regulation by Nkx2.2 is conserved in zebrafish, and loss-of-function studies in zebrafish reveal that, in contrast to Nkx2.2, tm4sf4 inhibits α and β cell specification but promotes ε cell fate. Finally, in vitro experiments indicate that Tm4sf4 inhibits Rho-activated cell migration. The researchers propose that the primary role of Nkx2.2 during pancreatic development is to inhibit Tm4sf4 in endocrine progenitor cells, thereby allowing their delamination, migration and differentiation. Targeting Tm4sf4 could, therefore, provide a way to activate quiescent pancreas progenitors for the treatment of diabetes.
