A CXCL12 kemokin és receptorának (CXCR4) szerepe az utóbélhez asszociált szövetekben zajló sejtvándorlási folyamatokban
Gáspár-Halasy Viktória
Molecular Medicine
Dr. Enyedi Péter
Általános Orvostudományi Kar Anatómiai, Szövet- és Fejlődéstani Intézet Huzella-tanterem
2024-11-22 14:00:00
Embryology, Theoretical, Experimental and Clinical Developmental Biology
Dr. Nagy Nándor
Dr. Nagy Nándor
Dr. Tőkés Anna-Mária
Sótiné Dr. Bagyánszki Mária
Dr. Mócsai Attila
Dr. Tóth Zsuzsanna Emese
Dr. Heinzlmann Andrea
The key role of the CXCL12 chemokine and its receptor, CXCR4 has been reported in the migration of multiple cell types. The migration of lymphocytes, cranial- and cardiac neural crest cells, and the mechanism of axon growth are regulated by this chemokine signaling. However, there is only indirect evidence and speculation regarding the role of CXCR4-CXCL12 of cervical- and lumbo-sacral neural crest cell movement for the establishment of the enteric nervous system (ENS). It was first observed in chicken embryos that the neurons and glial cells in the gastrointestinal tract, connected to extrinsic nerve fibers from peripheral ganglia, originate from the neural crest. The pelvic plexus, found in both mammals and avian, along with the avian-specific Remak ganglion, derive from the lumbo-sacral neural crest and contribute to the extrinsic innervation of the distal colon. Despite these insights, our understanding of the regulatory molecular mechanism involved in their development is still limited.
Our immunofluorescence analyses suggest that CXCR4 is not involved in the colonization processes of neural crest cells forming the ENS, but the CXCR4 receptor is specifically expressed in the Remak ganglion and pelvic plexus nerve fibers, whereas CXCL12 is detected in the smooth muscle, epithelium and the intrinsic neural plexuses of the hindgut. Using in vitro and ex vivo organ cultures, tissue recombination, and microbead implantation experiments, we have examined the roles of CXCR4 and CXCL12 in the development of the hindgut ENS. Increased doses of CXCL12 recombinant protein enhances axonal projection from the Remak-ganglion, whereas inhibiting CXCR4-CXCL12 signaling disrupts the growth of extrinsic nerve fibers towards the gut. Our results provide important insights into the pathogenesis of Hirschsprung-disease, a relatively common (1 in 5000) congenital neurointestinal disease where both intrinsic and extrinsic innervation of the distal colon are affected. In addition to our focus on colorectal ENS development, we demonstrated that CXCR4-CXCL12 signaling is also crucial for B-cell migration in the hindgut-associated primary lymphoid organ, the bursa of Fabricius, in chicken embryos. The central role of CXCR4-CXCL12 in neural crest and lymphoid precursor cell migration underscores the importance of precise spatio-temporal regulation of the chemokines in the development of hindgut-associated organs.
