Impaired Meningeal Development in Association with Apical Expansion of Calvarial Bone Osteogenesis in the Foxc1 Mutant

Loss of function of the mouse forkhead/winged helix transcription factor Foxc1 induces congenital hydrocephalus and impaired skull bone development due to failure of apical expansion of the bone. In this study we investigated meningeal development in the congenital hydrocephalus (ch) mouse with spontaneous loss of function mutant of Foxc1, around the period of initiation of skull bone apical expansion. In situ hybridization of Runx2 revealed active apical expansion of the frontal bone begins between embryonic day 13.5 and embryonic day 14.5 in the wild type, whereas expansion was inhibited in the mutant. Ultrastructural analysis revealed that three layers of the meninges begin to develop at E13.5 in the basolateral site of the head and subsequently progress to the apex in wild type. In ch homozygotes, although three layers were recognized at first at the basolateral site, cell morphology and structure of the layers became abnormal except for the pia mater, and arachnoidal and dural cells never differentiated in the apex. We identified meningeal markers for each layer and found that their expression was down-regulated in the mutant arachnoid and dura maters. These results suggest that there is a close association between meningeal development and the apical growth of the skull bones.