Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Essential Role of BMP4 Signaling in the Avian Ceca in Colorectal Enteric Nervous System Development

Tamás Kovács
ORCID logo ,
Viktória Halasy
,
Csongor Pethő
,
Emőke Szőcs
,
Ádám Soós
,
Dávid Dóra
,
De Santa Barbara Pascal
ORCID logo ,
Sandrine Faure
,
Rhian G Stavely
ORCID logo ,
Allan M Goldstein
,
Nándor Nagy
*
Version 1 : Received: 1 September 2023 / Approved: 4 September 2023 / Online: 5 September 2023 (02:47:26 CEST)

A peer-reviewed article of this Preprint also exists.

Kovács, T.; Halasy, V.; Pethő, C.; Szőcs, E.; Soós, Á.; Dóra, D.; de Santa Barbara, P.; Faure, S.; Stavely, R.; Goldstein, A.M.; Nagy, N. Essential Role of BMP4 Signaling in the Avian Ceca in Colorectal Enteric Nervous System Development. Int. J. Mol. Sci. 2023, 24, 15664. Kovács, T.; Halasy, V.; Pethő, C.; Szőcs, E.; Soós, Á.; Dóra, D.; de Santa Barbara, P.; Faure, S.; Stavely, R.; Goldstein, A.M.; Nagy, N. Essential Role of BMP4 Signaling in the Avian Ceca in Colorectal Enteric Nervous System Development. Int. J. Mol. Sci. 2023, 24, 15664.

Abstract

The enteric nervous system (ENS) is principally derived from vagal neural crest cells that migrate caudally along the entire length of the gastrointestinal tract, giving rise to neurons and glial cells in two ganglionated plexuses. Incomplete migration of enteric neural crest-derived cells (ENCDC) leads to Hirschsprung disease, a congenital disorder characterized by the absence of enteric ganglia along variable lengths of the colorectum. Our recent data [1] support an essential role for the avian ceca, present at the junction of midgut and hindgut, in hindgut ENS development, since ablation of the cecal buds leads to incomplete ENCDC colonization of the hindgut. In situ hybridization shows bone morphogenetic protein-4 (BMP4) highly expressed in the cecal mesenchyme, leading us to hypothesize that cecal BMP4 is required for hindgut ENS development. To test this, we modulated BMP4 activity using embryonic intestinal organ culture techniques and retroviral infection in ovo. We show that overexpression or inhibition of BMP4 in the ceca disrupts hindgut ENS development, with GDNF playing an important regulatory role. Our results suggest that these two important signaling pathways are required for normal ENCDC migration and enteric ganglion formation in the developing hindgut ENS.

Keywords

enteric nervous system; neural crest; ceca; hindgut; Hirschsprung disease; BMP4; Noggin; GDNF

Subject

Biology and Life Sciences, Cell and Developmental Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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