Combined effects of Ret coding and enhancer loss-of-function alleles cause progressive loss of inhibitory motor neurons in the enteric nervous system.

Combined Ret enhancer deletion and coding variants cause a 50% reduction in Ret expression, leading to selective loss of inhibitory motor neurons in the enteric nervous system.

• Why it matters: Understanding how genetic variants contribute to Hirschsprung disease (HSCR) is crucial because the disease results from disrupted development of enteric neural crest-derived cells, and the mechanisms linking genetic changes to specific cell type defects remain unclear.
• What they did: Researchers generated mice with a Ret enhancer deletion and a Ret null allele, then used single-cell RNA sequencing to analyze embryonic gut cells, revealing cell type-specific effects on Ret expression and neuron development.
• The result: The study found that combined genetic alterations cause a 50% decrease in Ret expression, resulting in depletion of inhibitory motor neuron lineages, which suggests HSCR may arise from cellular defects triggered by partial Ret loss.