Lmx1a functions in intestinal serotonin-producing enterochromaffin cells downstream of Nkx2.2

Abstract

The intestinal hormone-producing cells represent the largest endocrine system in the body; however, there is still remarkably little known about enteroendocrine cell type specification in the embryo and adult. We analyzed stage and cell-type specific deletions of Nkx2.2 and its functional domains to characterize its precise role in the development and maintenance of enteroendocrine cell lineages in the duodenum and colon. Although Nkx2.2 regulates enteroendocrine cell specification in the duodenum at all stages examined, Nkx2.2 controls the differentiation of progressively fewer enteroendocrine cell populations when deleted from Neurogenin 3 (Ngn3)+ progenitor cells or in the adult duodenum. During embryonic development Nkx2.2 regulates all enteroendocrine cell types, except gastrin and preproglucagon. In the developing Ngn3-expressing enteroendocrine progenitor cells, Nkx2.2 is also not required for the specification of neuropeptide Y and vasoactive intestinal polypeptide, indicating that a subset of these cell populations derive from an Nkx2.2-independent lineage. In the adult duodenum, Nkx2.2 also becomes dispensable for cholecystokinin and secretin production. In all stages and Nkx2.2 mutant conditions, serotonin-producing enterochromaffin cells were the most severely reduced enteroendocrine lineage in the duodenum and the colon. We determined that the transcription factor Lmx1a is expressed in enterochromaffin cells and functions downstream of Nkx2.2. Consistently, Lmx1a-deficient mice have reduced expression of Tph1, the rate-limiting enzyme for serotonin biosynthesis. These data clarify the function of Nkx2.2 in the specification and homeostatic maintenance of enteroendocrine populations, and identify Lmx1a as a novel enterochromaffin cell marker that is also essential for the production of the serotonin biosynthetic enzyme Tph1.