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

Loss of the Ret mcs+9.7 enhancer combined with Ret coding variants causes a 50% reduction in Ret expression, leading to selective depletion of inhibitory motor neurons in the ENS.

• Why it matters: Understanding how genetic variants influence specific neuron subtypes in the enteric nervous system is crucial for unraveling the mechanisms behind Hirschsprung disease and developing targeted therapies.
• What they did: Researchers used mouse models with enhancer deletions and Ret null alleles, performing single-cell RNA sequencing to assess effects on ENS cell types and gene expression, focusing on Ret dosage and neuron differentiation.
• The result: Findings show that combined genetic perturbations cause cell type-specific Ret reduction, disrupting inhibitory motor neuron development without gross ENS loss, highlighting a cascade of cellular defects underlying HSCR.