Abstract
Decades ago, investigators reported that mice lacking DLX1 and DLX2, transcription factors expressed in the enteric nervous system (ENS), die with possible bowel motility problems. These problems were never fully elucidated. We found that mice lacking DLX1 and DLX2 (Dlx1/2-/- mice) had slower small bowel transit and reduced or absent neurally mediated contraction complexes. In contrast, small bowel motility seemed normal in adult mice lacking DLX1 (Dlx1-/-). Even with detailed anatomic studies, we found no defects in ENS precursor migration, or neuronal and glial density in Dlx1/2-/- or Dlx1-/- mice. However, RNA sequencing of Dlx1/2-/- ENS revealed dysregulation of many genes, including vasoactive intestinal peptide (Vip). Using immunohistochemistry and reporter mice, we then found that Dlx1/2-/- mice have reduced VIP expression and fewer VIP-lineage neurons in their ENS. Our study reveals what we believe is a novel connection between Dlx genes and Vip and highlights the observation that dangerous bowel motility problems can occur in the absence of easily identifiable ENS structural defects. These findings may be relevant for disorders like chronic intestinal pseudo-obstruction (CIPO) syndrome.
Highlights
Chronic intestinal pseudo-obstruction (CIPO) is a serious digestive disorder characterized by profound bowel motility defects, leading to severe constipation, abdominal distention, and life-threatening malnutrition requiring total parenteral nutrition (TPN)
CIPO describes a poorly understood constellation of diseases in which bowel motility is abnormal despite the presence of neurons throughout the bowel
Our study provides an example of how bowel motility defects may occur in the absence of identified enteric nervous system (ENS) structural defects, likely due to gene-level dysregulation
Summary
Chronic intestinal pseudo-obstruction (CIPO) is a serious digestive disorder characterized by profound bowel motility defects, leading to severe constipation, abdominal distention, and life-threatening malnutrition requiring total parenteral nutrition (TPN). Many CIPO cases are believed to be caused by defects in the enteric nervous system (ENS), a complex network of neurons and glia within the bowel wall [3]. In neuropathic CIPO, neurons and glia are present, but damaged or dysfunctional, leading to dysmotility. Neuronal dysfunction in CIPO has many etiologies, including infection, autoimmune disease, neurodegeneration, and gene mutations [1, 6]. Genes like SOX10 and POLG have been linked to neuropathic CIPO [7, 8], we believe many CIPOlinked genes remain to be discovered [9]. We discovered that loss of these genes in mice causes profound intestinal dysmotility despite nearly normal ENS anatomy
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