The developmental etiology and pathogenesis of Hirschsprung disease

Abstract

The enteric nervous system is the part of the autonomic nervous system that directly controls the gastrointestinal tract. Derived from a multipotent, migratory cell population called the neural crest, a complete enteric nervous system is necessary for proper gut function. Disorders that arise as a consequence of defective neural crest cell development are termed neurocristopathies. One such disorder is Hirschsprung disease (HSCR), also known as congenital megacolon or intestinal aganglionosis. HSCR occurs in 1/5000 live births and typically presents with the inability to pass meconium, along with abdominal distension and discomfort that usually requires surgical resection of the aganglionic bowel. This disorder is characterized by a congenital absence of neurons in a portion of the intestinal tract, usually the distal colon, because of a disruption of normal neural crest cell migration, proliferation, differentiation, survival, and/or apoptosis. The inheritance of HSCR disease is complex, often non-Mendelian, and characterized by variable penetrance. Extensive research has identified a number of key genes that regulate neural crest cell development in the pathogenesis of HSCR including RET, GDNF, GFRα1, NRTN, EDNRB, ET3, ZFHX1B, PHOX2b, SOX10, and SHH. However, mutations in these genes account for only ∼50% of the known cases of HSCR. Thus, other genetic mutations and combinations of genetic mutations and modifiers likely contribute to the etiology and pathogenesis of HSCR. The aims of this review are to summarize the HSCR phenotype, diagnosis, and treatment options; to discuss the major genetic causes and the mechanisms by which they disrupt normal enteric neural crest cell development; and to explore new pathways that may contribute to HSCR pathogenesis.

Figure 1. Enteric neuron immunostaining in wild-type embryonic guts

Tuj1 (red) immunostaining of E11.5 to E14.5 whole guts shows wavefront location. At E11.5, the embryonic gut is in a hairpin formation and neurons are present to the cecum. At E12.5 the gut has grown, and the neurons have reached the proximal hindgut. The E12.5 gut pictured is a back-side view to visualize the wavefront. At E14.5 neurons have reached the distal hindgut and grown significantly and the hairpin formation is no longer present. Asterisk (*) marks the mesentery at E12.5 through which tmENCCs migrate. Nuclei are counterstained with 4′,6-diamidino-2-phenylindole (DAPI) (blue).

Figure 2. Trans-mesenteric enteric neural crest cells migrate through the mesentery of E11.75 guts

Whole-mount co-immunostain of GFP and Tuj1 staining of E11.75 gut from a Rosa^eYFP; Wnt1Cre embryo. White arrows depict tmENCCs in the mesentery between the midgut and hindgut. Mesentery is located between dotted lines. Neural crest cells are stained with GFP and mature neurons are stained with Tuj1 (red). Nuclei are counterstained with 4′,6-diamidino-2-phenylindole (DAPI) (blue).