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 5

P15 TyrBap1 KO enteric neuron density is low in all regions with disproportionate Tyr-Cre–lineage and cholinergic neuron loss.

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P15 TyrBap1 KO enteric neuron density is low in all regions with disprop...
(A and B) P15 TyrBap1 KO neuron density is lower than WT in myenteric (A) and submucosal plexus (B) in all regions. (C) P15 Tyr-Cre–lineage (TdTomato+) myenteric plexus neurons are disproportionately reduced in all regions of TyrBap1 KO. Tyr-Cre–lineage submucosal neurons are disproportionately reduced only in PSI. (D and E) P15 TyrBap1 KO cholinergic neuron density is reduced in myenteric (D) and submucosal plexus (E) in all regions. (F) Cholinergic neurons are disproportionately reduced for P15 TyrBap1 KO in all myenteric plexus regions but not in submucosal plexus. (G and H) P15 TyrBap1 KO nitrergic neuron (NOS1-expressing neuron) density is reduced in all myenteric (G) and submucosal plexus (H) regions evaluated. (I) Proportion of nitrergic neurons is similar in TyrBap1 KO and WT in all regions. (D–F) Cholinergic neurons are defined as GFP+ using TyrBap1 Chat-GFP interbred lines. (A–I) WT is Bap1wt/wt Tyr-Cre+. PSI, proximal small intestine; DSI, distal small intestine; PCO, proximal colon; DCO, distal colon. Data are represented as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. (A and B, PSI, DSI, and PCO): Unpaired 2-tailed t test with Welch’s correction. (B, DCO, and E): Two-tailed Mann-Whitney test. (C) Two-tailed unpaired t test with Welch’s correction. (D and G) Welch’s 2-tailed unpaired t test. (F) Welch’s 2-tailed unpaired t test, except for PCO, which used 2-tailed Mann-Whitney test. (H) Welch’s 2-tailed unpaired t test, except PSI, which used Mann-Whitney test. (I) Welch’s 2-tailed unpaired t test, except DSI, which used 2-tailed Mann-Whitney test.