BAP1 is required prenatally for differentiation and maintenance of postnatal murine enteric nervous system
Sabine Schneider, … , J. William Harbour, Robert O. Heuckeroth
Sabine Schneider, … , J. William Harbour, Robert O. Heuckeroth
Published May 1, 2024
Citation Information: J Clin Invest. 2024;134(9):e177771. https://doi.org/10.1172/JCI177771.
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Research Article Development Gastroenterology

BAP1 is required prenatally for differentiation and maintenance of postnatal murine enteric nervous system

Abstract

Epigenetic regulatory mechanisms are underappreciated, yet are critical for enteric nervous system (ENS) development and maintenance. We discovered that fetal loss of the epigenetic regulator Bap1 in the ENS lineage caused severe postnatal bowel dysfunction and early death in Tyrosinase-Cre Bap1fl/fl mice. Bap1-depleted ENS appeared normal in neonates; however, by P15, Bap1-deficient enteric neurons were largely absent from the small and large intestine of Tyrosinase-Cre Bap1fl/fl mice. Bowel motility became markedly abnormal with disproportionate loss of cholinergic neurons. Single-cell RNA sequencing at P5 showed that fetal Bap1 loss in Tyrosinase-Cre Bap1fl/fl mice markedly altered the composition and relative proportions of enteric neuron subtypes. In contrast, postnatal deletion of Bap1 did not cause enteric neuron loss or impaired bowel motility. These findings suggest that BAP1 is critical for postnatal enteric neuron differentiation and for early enteric neuron survival, a finding that may be relevant to the recently described human BAP1-associated neurodevelopmental disorder.

Authors

Sabine Schneider, Jessica B. Anderson, Rebecca P. Bradley, Katherine Beigel, Christina M. Wright, Beth A. Maguire, Guang Yan, Deanne M. Taylor, J. William Harbour, Robert O. Heuckeroth

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Figure 2

Proximal small intestine and colon motility are significantly impaired in P15 TyrBap1 KO mice.

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Proximal small intestine and colon motility are significantly impaired i...
(A) TyrBap1 KO have slow transit of FITC-dextran through proximal small bowel. Mean FITC fluorescence distribution ± SEM 90 minutes after gavage. Numbered segments of bowel from stomach (segment 1) to distal rectum (segment 19) are arranged along the x axis. (B) Geometric center of FITC fluorescence was more proximal for TyrBap1 KO than for Het and WT. Numbered bowel segments are indicated on the y axis. SI, small intestine. (C) P15 TyrBap1 KO passed few stool pellets over 8 hours compared with Het or WT. (D) Most P15 TyrBap1 KO had abnormal stool (diarrhea or no feces at all). (E and F) Representative kymographs depicting bowel width as a function of time and distance along proximal-distal axis of cannulated colon for P15 WT (E) and TyrBap1 KO (F). (G) Fewer colonic motor complexes were recorded for TyrBap1 KO as compared with Het and WT colons. (A–G) Het refers to Bap1fl/wt Tyr-Cre+ genotype, and KO refers to TyrBap1 KO. (A and B) WT includes Bap1wt/wt Tyr-Cre+ genotype and mice lacking Cre. (C–G) WT refers to Bap1wt/wt; Tyr-Cre+ genotype. (B, C, and G) Data are shown as mean ± SD. Data not significant unless otherwise indicated. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. (B) Welch’s ANOVA test with multiple comparisons. (C and E–G) Kruskal-Wallis test with Dunn’s multiple comparison. (D) Two-sided binomial test.