Molecular and Cell Biological Mechanisms of Neural Differentiation of the Enteric Nervous System in Gastroschisis

• Applicant: Dr. Peter Neckel
• Subject Area: Pediatric and Adolescent Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 554598887

Gastroschisis is a rare congenital abdominal wall defect by which small bowel segments are herniated and directly exposed to the amniotic fluid in utero. Despite successful surgical intervention after birth, a considerable percentage of patients is suffering from severe intestinal motility dysfunctions regularly leading to long-term conditions with high morbidity. Yet, the pathomechanisms underlying gastroschisis-related dysmotility are little investigated and remain enigmatic. Gastrointestinal motility is controlled by a complex interplay of the gut-resident enteric nervous system (ENS) and myogenic pacemaker cells called interstitial cells of Cajal (ICCs). Thus, in the proposed project, we hypothesize that the structure and functionality of ENS-ICC network is severely hampered leading to gastroschisis-associated dysmotility. In our first work package, we aim to elucidate the functional histo-architecture and ultrastructure of the ENS-ICC network in intestinal resectates from gastroschisis patients compared to matched controls. While the current knowledge is solely based on sparse single-case studies or unsatisfactory rodent models, our approach uses modern immunolabeling and microscopic imaging techniques as well as electron microscopic interrogation on a collection of patient samples, which is unprecedented in the study of this disorder. Moreover (work package 2), we want to isolate and culture murine and human ENS cells to elucidate the proliferative capacity, differentiation patterns, and cell biology in a novel approach to model gastroschisis in vitro. This will be complemented by in-ovo-experiments on ENS-development under gastroschisis-conditions based on CAM-transplantation assays (work package 3). Comparable investigations are unprecedented and will help us to understand the fundamental pathology of gastroschisis-related dysmotilities on cellular and molecular level. Additionally, these in-vitro- and in-ovo-systems will be useful for future pharmacological and functional studies targeting to improve the therapy of gastroschisis-related intestinal dysfunctions.

• DFG Programme: Research Grants