Impaired proliferative activity of mesenchymal cells affects the migratory pathway for neural crest cells in the developing gut of mutant murine embryos.

The developmental expression of neural and cell proliferation-related antigens in guts from mutant murine embryos (Is, lethal spotted) as a model for Hirschsprung's disease was studied. The expression was examined immunohistochemically using antibodies specific for neural cell adhesion molecule (NCAM), the L1 molecule, and proliferative cell-related nuclear antigen (PCNA). Cells immunoreactive for neural components proceeded from the esophagus to the anorectum showing a one-way migratory wave between embryonal day 10 (E10) and E14 in control specimens (Is/+, +/+). The patterns of NCAM and L1 immunoreactivity in Is/Is mutant specimens was the same as in controls on E10. However, from E10.5 to E13.5, the immunoreactivity in the mutants decreased and remained in the more oral side as compared with controls. No migration of immunoreactivity was found after E14.0. Therefore, the terminal portion of the colon remained aganglionic in Is/Is mutant embryos. PCNA immunoreactivity of mesenchymal cells preceded the migratory wave of the neural specific immunoreactivity, but the PCNA-positive cells were meager and poorly organized in the mutant embryos. Deficient PCNA staining patterns were found in mesenchymal tissue rather than in the migrating cells themselves. This impaired PCNA expression may reflect a deficient microenvironment for migration such that neural crest cells cannot colonize properly.