Novel Function of the Ciliogenic Transcription Factor RFX3 in Development of the Endocrine Pancreas

Abstract

The transcription factor regulatory factor X (RFX)-3 regulates the expression of genes required for the growth and function of cilia. We show here that mouse RFX3 is expressed in developing and mature pancreatic endocrine cells during embryogenesis and in adults. RFX3 expression already is evident in early Ngn3-positive progenitors and is maintained in all major pancreatic endocrine cell lineages throughout their development. Primary cilia of hitherto unknown function present on these cells consequently are reduced in number and severely stunted in Rfx3−/− mice. This ciliary abnormality is associated with a developmental defect leading to a uniquely altered cellular composition of the islets of Langerhans. Just before birth, Rfx3−/− islets contain considerably less insulin-, glucagon-, and ghrelin-producing cells, whereas pancreatic polypeptide–positive cells are markedly increased in number. In adult mice, the defect leads to small and disorganized islets, reduced insulin production, and impaired glucose tolerance. These findings suggest that RFX3 participates in the mechanisms that govern pancreatic endocrine cell differentiation and that the presence of primary cilia on islet cells may play a key role in this process.