Cell-autonomous retinoic acid receptor signaling has stage-specific effects on mouse enteric nervous system

Abstract

Retinoic acid (RA) signaling is essential for enteric nervous system (ENS) development since vitamin A deficiency or mutations in RA signaling profoundly reduce bowel colonization by ENS precursors. These RA effects could occur because of RA activity within the ENS lineage or via RA activity in other cell types. To define cell-autonomous roles for retinoid signaling within the ENS lineage at distinct developmental time points, we activated a potent floxed dominantnegative RA receptor α (RarαDN) in the ENS using diverse CRE recombinase-expressing mouse lines. This strategy enabled us to block RA signaling at pre-migratory, migratory, and postmigratory stages for ENS precursors. We found that cell-autonomous loss of retinoic acid receptor (RAR) signaling dramatically affects ENS development. CRE activation of RarαDN expression at pre-migratory or migratory stages caused severe intestinal aganglionosis, but at later stages, RarαDN induced a broad range of phenotypes including hypoganglionosis, submucosal plexus loss, and abnormal neural differentiation. RNA-sequencing highlighted distinct RA-regulated gene sets at different developmental stages. These studies show complicated context-dependent RAmediated regulation of ENS development.

Roles of Enteric Neural Stem Cell Niche and Enteric Nervous System Development in Hirschsprung Disease

“…Retinoic acid (RA) signalling is essential for normal ENS development. Vitamin A deficiency in Rbp –/– mutant mouse model caused distal bowel aganglionosis and cell-autonomous loss of RA receptor signalling affected ENCC migration and differentiation in a stage-specific and context-dependent manner [ 55 , 56 ]. Retinoic acid is therefore important not only in ENS precursor induction and specification in cell-based therapy, but also in modulating migration and neurogenesis after transplantation.…”

BAP1 is required prenatally for differentiation and maintenance of postnatal murine enteric nervous system

“…In contrast, Vip and Slc18a3 were more abundant in TyrBap1 KO myenteric neurons than in WT. Rarb ( 21 ) and Cntfr ( 47 ), which influence enteric neuron subtype differentiation, were also more abundant in TyrBap1 KO compared with WT neurons. The many differences in gene expression between WT and TyrBap1 KO are likely to affect neuron function, differentiation, and survival.…”

“…RA is derived from vitamin A. Both vitamin A deficiency ( 20 ) and expression of a dominant-negative RAR ( 21 ) in the ENS cause distal bowel aganglionosis. Moreover, RA signaling impacts enteric neuron differentiation ( 22 ).…”

Signaling pathways in the control of embryonic development of the enteric nervous system

“…Naime, mezenhimalne ćelije somita sekretuju povećanu količinu retinoične kiseline, koja aktivacijom svojih nuklearnih receptora, pre svega RARα (Retinoic Acid Receptor alpha), podstiče ekspresiju RET receptora na površini ćelija poreklom od nervnog grebena. Ovo će opredeliti prekursorske ćelije da migriraju ka budućem gastrointestinalnom traktu i daju ćelije ENS (15). Za ekrpesiju RET receptora na prekursorskim ćelijama ENS neophodna je aktivnost transkripcionih faktora SOX10 (SRY-box transcription factor 10), PHOX2B (Paired-like Homeobox 2B) i PAX3 (Paired Box3) (Slika 1) (13).…”

“…Namely, mesenchymal somite cells produce higher levels of retinoic acid, which by activating its nuclear receptors, first of all RARα (Retinoic Acid Receptor α), enhances the expression of RET receptor on the surface of cells derived from the neural crest. This will make precursor cells migrate towards the future gastrointestinal tract and give ENS cells (15). The activity of transcription factors SOX10 (SRY-box transcription factor 10), PHOX2B (Paired-like Homeobox 2B) and PAX3 (Paired box 3) is necessary for the expression of RET receptors on ENS precursor cells (Figure 1) (13).…”