Developmental role of embryonic ceca in hindgut enteric nervous system formation
Kovács Tamás
Molecular Medicine Division
Dr. Várnai Péter
SE Neurológiai és Pszichiátriai Klinika közös tanterme
2026-01-27 12:00:00
Embryology, Theoretical, Experimental and Clinical Developmental Biology
Dr. Nagy Nándor
Dr. Nagy Nándor
Dr. Apáti Ágota
Dr. Bagyánszki Mária
Dr. Várnai Péter
Dr. Zachar Gergely
Dr. Kovács Tibor
The enteric nervous system (ENS), originating from enteric neural crest-derived cells (ENCDCs), forms the complex neuronal innervation of the gastrointestinal tract. Disruption of ENCDC migration can result in Hirschsprung disease, characterized by the absence of enteric ganglia in the distal colorectum. We observed that ENCDC proliferation is specifically high during their migration throughout the ceca, a paired structure of the avian intestine at the midgut-hindgut junction level. Microsurgical ablation of the ceca leads to hindgut aganglionosis, highlighting their essential role in colorectal ENS development. Comparative transcriptomic analysis revealed that non-canonical Wnt signaling, especially WNT11, is highly expressed in the ceca mesenchyme. RNA in situ hybridization confirmed the ceca mesenchyme-specific expression of the WNT11 gene. Addition of recombinant WNT11 protein in organ culture experiments showed to inhibit enteric neuronal differentiation, suggesting a role in maintaining ENCDCs in the undifferentiated progenitor state. Furthermore, transcriptomic profiling also identified bone morphogenetic proteins (BMPs) as critical regulators. In situ hybridization revealed strong BMP4 expression in the cecal mesenchyme, suggesting a critical role for cecal-derived BMP4 in hindgut ENS formation. To investigate this, we modulated BMP4 activity using embryonic intestinal organ culture and retroviral-mediated gene manipulation. Both overexpression and inhibition of BMP4 in the ceca disrupted hindgut ENS development, indicating that precise regulation of BMP4 is necessary. Our findings demonstrate that BMP, non-canonical WNT and GDNF signaling pathways are essential for normal ENCDC migration and enteric ganglia formation in the hindgut. This study identifies novel molecular players in avian hindgut ENS development and provides new insights into the regulation of ENCDC proliferation, migration, and differentiation.
