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 exami ned immunohistochemically using antibodies specific for neural cell ad hesion molecule (NCAM), the L1 molecule, and proliferative cell-relate d nuclear antigen (PCNA). Cells immunoreactive for neural components p roceeded from the esophagus to the anorectum showing a one-way migrato ry wave between embryonal day 10 (E10) and E14 in control specimens (I s/+, +/+). The patterns of NCAM and L1 immunoreactivity in Is/Is mutan t 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 immunore activity was found after E14.0. Therefore, the terminal portion of the colon remained aganglionic in Is/Is mutant embryos. PCNA immunoreacti vity of mesenchymal cells preceded the migratory wave of the neural sp ecific immunoreactivity, but the PCNA-positive cells were meager and p oorly organized in the mutant embryos. Deficient PCNA staining pattern s were found in mesenchymal tissue rather than in the migrating cells themselves. This impaired PCNA expression may reflect a deficient micr oenvironment for migration such that neural crest cells cannot coloniz e properly.