bHLH proneural genes as cell fate determinants of entero-endocrine cells, an evolutionarily conserved lineage sharing a common root with sensory neurons

Abstract

Entero-endocrine cells involved in the regulation of digestive function form a large and diverse cell population within the intestinal epithelium of all animals. Together with absorptive enterocytes and secretory gland cells, entero-endocrine cells are generated by the embryonic endoderm and, in the mature animal, from a pool of endoderm derived, self-renewing stem cells. Entero-endocrine cells share many structural/functional and developmental properties with sensory neurons, which hints at the possibility of an ancient evolutionary relationship between these two cell types. We will survey in this article recent findings that emphasize the similarities between entero-endocrine cells and sensory neurons in vertebrates and insects, for which a substantial volume of data pertaining to the entero-endocrine system has been compiled. We will then report new findings that shed light on the specification and morphogenesis of entero-endocrine cells in Drosophila. In this system, presumptive intestinal stem cells (pISCs), generated during early metamorphosis, undergo several rounds of mitosis that produce the endocrine cells and stem cells (ISCs) with which the fly is born. Clonal analysis demonstrated that individual pISCs can give rise to endocrine cells expressing different types of peptides. Immature endocrine cells start out as unpolarized cells located basally of the gut epithelium; they each extend an apical process into the epithelium which establishes a junctional complex and apical membrane specializations contacting the lumen of the gut. Finally, we show that the Drosophila homolog of ngn3, a bHLH gene that defines the entero-endocrine lineage in mammals, is expressed and required for the differentiation of this cell type in the fly gut.

Anatomy and Physiology of the Digestive Tract of Drosophila melanogaster

“…At least 95% of them express peptide hormones, often more than one and with regional stereotypy ( Veenstra et al 2008 ; Veenstra 2009 ; Reiher et al 2011 ; Beehler-Evans and Micchelli 2015 ). The developmental program of EE cells shares similarities with that of neurons, probably reflecting a common phylogenetic origin ( Hartenstein 2006 ; Hartenstein et al 2010 , 2017 ). Consistent with this idea, all known EE peptide hormones (possibly with the exception of one of the insect CCHamides; S. Li et al 2013 ) are also produced by the brain.…”

You Are What You (First) Eat

“…Nonetheless, like other sensory epithelial cells of endodermal origin, enteroendocrine cells have prominent neuronal features. They are electrically excitable (Rogers et al, 2011 ), form synapses (Bohórquez et al, 2015 ), and release neuropeptides and neurotransmitters in response to stimuli (Hartenstein et al, 2017 ). Because of the mounting evidence that these cells act as true epithelial transducers, further exploration will elucidate the precise origin of these cells.…”

“…The first enteroendocrine cells appear early in gestation, during gut tube development. At this point the cells remain mitotically active (Crosnier, 2005 ; Penkova et al, 2010 ; Hartenstein et al, 2017 ). Upon folding of the gut epithelium into crypts and villi, most cells are differentiated, and further proliferation occurs from the Lgr5-expressing adult stem cells of the crypts (Barker et al, 2007 ).…”

Evolution of nitric oxide regulation of gut function

“…However, endoderm-derived cells, which contain neurotransmitters and hormones, are categorized as enteroendocrine cells in vertebrate digestive tracts (3,49). Some enteroendocrine cells have axon-like processes, which are shorter than neuronal axons, and target the gut lumen and enteric neurons on the basal side of the gut wall (49,50). It is also reported that hormones released from enteroendocrine cells regulate the contraction and relaxation of the pyloric sphincter (51).…”

“…Because sEN in sea urchin larvae shares some of these morphological and functional characteristics, we cannot conclude that SynBpositive cells are neurons or enteroendocrine cells. It has been suggested that peripheral sensory neurons and enteroendocrine cells share common origins (50), which makes the difference indistinct. Although we are unable to fully distinguish the nature of these cells, sea urchin nNOS-positive endoderm-derived cells suggests an evolutionary history in which the common deuterostome ancestor had endodermally derived cells that regulated gut function.…”