Human enteric nervous system progenitor dynamics during development and disease

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The proper function of our gut is controlled, in an involuntary fashion, by a complex network of nerves, the enteric nervous system (ENS), also known as the 'second brain'. The ENS is produced in utero by specialised cell populations known as ENS progenitors and Schwann cell precursors (SCPs). Mistakes in the generation of the ENS by these progenitors, often due to defects in our DNA (mutations), lead to birth conditions called enteric neuropathies that are marked by lack of nerves in the gut. The most common enteric neuropathy is Hirschsprung disease, which is a life-threatening intestinal disorder affecting approximately 1 in 5,000 newborn children. The lack of enteric nerves in Hirschsprung disease is usually caused by mutations in a gene called RET, which is important for the proper function of ENS progenitors. Strikingly, RET mutations do not seem to affect SCPs, the other complementary source of ENS cells. To better understand the causes of HSCR, it is therefore important to examine how ENS progenitors/SCPs produce enteric nerves and how RET mutations affect this process. To address this issue, we propose to use human stem cells to generate healthy and RET-mutant ENS progenitors and SCPs, and kept in culture in a petri dish. We will then study in detail the behaviour of the RET-mutant cell populations after their injection in gut tissue isolated from human patients and mice, and grown in the petri dish. Comparison of mutant and healthy cells will help us understand what goes wrong in Hirschsprung disease and will ultimately assist the development of therapies against this devastating childhood disease.