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 3

Neonatal Wnt1Bap1+ mice have normal enteric neuron density and proximal small intestinal motility.

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Neonatal Wnt1Bap1+ mice have normal enteric neuron density and proximal ...
(A–C) Enteric neuron density is similar to WT in most bowel regions in P0 Wnt1Bap1 KO (KO). (A) Representative maximal-intensity projection Z-stacks of WT (top) and KO (bottom) along the bowel. Purple, HuC/D; green, TuJ1. Scale bar: 100 μm. (B) Quantification of P0 myenteric neuron density. (C) Quantification of P0 submucosal enteric neuron density. (D, E, G, and H) Representative kymographs depicting bowel width as a function of time and distance along proximal-distal axis proximal small intestine for P0 control (Ctrl; D and E) and KO (G and H). Low-frequency (LF) contractions (neurogenic) could be recorded for a subset of P0 Ctrl and KO pups (D and G, white arrows), while no LF contractions were detected for other Ctrl and KO (E and H). (F) Proportion of bowels where any LF contractions were recorded did not differ between P0 Ctrl and P0 KO. (I) Frequency of LF contractions did not differ between Ctrl and KO neonates if any LF contractions could be recorded. Data points from Hets are red. (A–C) WT refers to Bap1wt/wt Wnt1-Cre+ or any genotype without the Wnt1-Cre transgene. Het refers to Bap1fl/wt Wnt1-Cre+ genotype. KO refers to Bap1fl/fl Wnt1-Cre+ genotype. Data not significant unless otherwise indicated. (D–I) Ctrl refers to any genotype without the Wnt1-Cre transgene, or Bap1wt/wt Wnt1-Cre+ or Bap1fl/wt Wnt1-Cre+ genotype. KO refers to Wnt1Bap1 KO genotype. (B and C) PSI, proximal small intestine; DSI, distal small intestine; PCO, proximal colon; DCO, distal colon. (B, C, and I) Data are shown as mean ± SD. (B and C) Welch’s ANOVA test with Dunnett’s T3 multiple-comparison test. (I) Two-sided Student’s t test.