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1.
J Clin Invest ; 134(9)2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38690732

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.


Subject(s)
Cell Differentiation , Enteric Nervous System , Tumor Suppressor Proteins , Ubiquitin Thiolesterase , Animals , Enteric Nervous System/metabolism , Enteric Nervous System/pathology , Mice , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Neurons/metabolism , Neurons/pathology , Mice, Knockout , Female , Gastrointestinal Motility/genetics , Humans
2.
JCI Insight ; 6(10)2021 05 24.
Article in English | MEDLINE | ID: mdl-33848271

ABSTRACT

Retinoic acid (RA) signaling is essential for enteric nervous system (ENS) development, since vitamin A deficiency or mutations in RA signaling profoundly reduce bowel colonization by ENS precursors. These RA effects could occur because of RA activity within the ENS lineage or via RA activity in other cell types. To define cell-autonomous roles for retinoid signaling within the ENS lineage at distinct developmental time points, we activated a potent floxed dominant-negative RA receptor α (RarαDN) in the ENS using diverse CRE recombinase-expressing mouse lines. This strategy enabled us to block RA signaling at premigratory, migratory, and postmigratory stages for ENS precursors. We found that cell-autonomous loss of RA receptor (RAR) signaling dramatically affected ENS development. CRE activation of RarαDN expression at premigratory or migratory stages caused severe intestinal aganglionosis, but at later stages, RarαDN induced a broad range of phenotypes including hypoganglionosis, submucosal plexus loss, and abnormal neural differentiation. RNA sequencing highlighted distinct RA-regulated gene sets at different developmental stages. These studies show complicated context-dependent RA-mediated regulation of ENS development.


Subject(s)
Enteric Nervous System , Receptors, Retinoic Acid , Signal Transduction , Animals , Embryo, Mammalian/innervation , Embryo, Mammalian/metabolism , Embryonic Development/genetics , Embryonic Development/physiology , Enteric Nervous System/embryology , Enteric Nervous System/metabolism , Female , Male , Mice , Neurogenesis/genetics , Neurogenesis/physiology , Receptors, Retinoic Acid/genetics , Receptors, Retinoic Acid/metabolism , Signal Transduction/genetics , Signal Transduction/physiology
3.
Cell Mol Gastroenterol Hepatol ; 11(5): 1548-1592.e1, 2021.
Article in English | MEDLINE | ID: mdl-33444816

ABSTRACT

BACKGROUND AND AIMS: Bowel function requires coordinated activity of diverse enteric neuron subtypes. Our aim was to define gene expression in these neuron subtypes to facilitate development of novel therapeutic approaches to treat devastating enteric neuropathies, and to learn more about enteric nervous system function. METHODS: To identify subtype-specific genes, we performed single-nucleus RNA-seq on adult mouse and human colon myenteric plexus, and single-cell RNA-seq on E17.5 mouse ENS cells from whole bowel. We used immunohistochemistry, select mutant mice, and calcium imaging to validate and extend results. RESULTS: RNA-seq on 635 adult mouse colon myenteric neurons and 707 E17.5 neurons from whole bowel defined seven adult neuron subtypes, eight E17.5 neuron subtypes and hundreds of differentially expressed genes. Manually dissected human colon myenteric plexus yielded RNA-seq data from 48 neurons, 3798 glia, 5568 smooth muscle, 377 interstitial cells of Cajal, and 2153 macrophages. Immunohistochemistry demonstrated differential expression for BNC2, PBX3, SATB1, RBFOX1, TBX2, and TBX3 in enteric neuron subtypes. Conditional Tbx3 loss reduced NOS1-expressing myenteric neurons. Differential Gfra1 and Gfra2 expression coupled with calcium imaging revealed that GDNF and neurturin acutely and differentially regulate activity of ∼50% of myenteric neurons with distinct effects on smooth muscle contractions. CONCLUSION: Single cell analyses defined genes differentially expressed in myenteric neuron subtypes and new roles for TBX3, GDNF and NRTN. These data facilitate molecular diagnostic studies and novel therapeutics for bowel motility disorders.


Subject(s)
Biomarkers/analysis , Enteric Nervous System/metabolism , Gene Expression Regulation , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Neurturin/metabolism , Single-Cell Analysis/methods , T-Box Domain Proteins/metabolism , Adult , Aged , Aged, 80 and over , Animals , Female , Glial Cell Line-Derived Neurotrophic Factor/genetics , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Neurturin/genetics , RNA-Seq/methods , T-Box Domain Proteins/genetics , Young Adult
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