Planar cell polarity genes control the connectivity of enteric neurons
Valentina Sasselli, … , André M. Goffinet, Vassilis Pachnis
Valentina Sasselli, … , André M. Goffinet, Vassilis Pachnis
Published March 8, 2013
Citation Information: J Clin Invest. 2013;123(4):1763-1772. https://doi.org/10.1172/JCI66759.
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Research Article Gastroenterology

Planar cell polarity genes control the connectivity of enteric neurons

Abstract

A highly complex network of intrinsic enteric neurons is required for the digestive and homeostatic functions of the gut. Nevertheless, the genetic and molecular mechanisms that regulate their assembly into functional neuronal circuits are currently unknown. Here we report that the planar cell polarity (PCP) genes Celsr3 and Fzd3 are required during murine embryogenesis to specifically control the guidance and growth of enteric neuronal projections relative to the longitudinal and radial gut axes. Ablation of these genes disrupts the normal organization of nascent neuronal projections, leading to subtle changes of axonal tract configuration in the mature enteric nervous system (ENS), but profound abnormalities in gastrointestinal motility. Our data argue that PCP-dependent modules of connectivity established at early stages of enteric neurogenesis control gastrointestinal function in adult animals and provide the first evidence that developmental deficits in ENS wiring may contribute to the pathogenesis of idiopathic bowel disorders.

Authors

Valentina Sasselli, Werend Boesmans, Pieter Vanden Berghe, Fadel Tissir, André M. Goffinet, Vassilis Pachnis

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Figure 6

Subtle deficits of fiber tracts in the ENS of Celsr3|Wnt1 mice.

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Subtle deficits of fiber tracts in the ENS of Celsr3|Wnt1 mice. (A and...
(A and B) Control and Celsr3|Wnt1 ileum immunolabeled for GFP (green), c-Kit (red), α-SMA (blue), and counterstained for DAPI (gray). (C and D) Myenteric ganglia from control and Celsr3|Wnt1 mice immunostained for HuC/D (magenta) and nNOS (green, C), or calretinin (green, D). (E) Density of HuC/D+ neurons and proportion of nNOS+ and calretinin+ neurons in the gut of control and Celsr3|Wnt1 mice (n ≥ 1,200). The Student’s t test was nonsignificant. (F and G) Grayscale images of myenteric plexus from control and Celsr3|Wnt1 mice immunostained for TuJ1. The longitudinal trajectory of TuJ1+ interganglionic strands is often lost in Celsr3|Wnt1 mutants (G). (H and I) DiI tracing of adult myenteric plexus from gut preparations that correspond to F and G, respectively. Images in H and I correspond to the boxed areas of the insets. (J and K) Triple labeling of myenteric plexus for nNOS (red), vAChT (green), and HuC/D (blue). In mutants, longitudinal nNOS+ strands were reduced in number and thickness (arrows), while vAChT+ fibers were unaffected. cm, circular muscle; lm, longitudinal muscle; mu, mucosa. Scale bars: 50 μm (A–D), 200 μm (F–K), and 500 μm (H and I insets).