Background: Folic acid is essential for the development of the nervous system and other associated structures. Mice deficient in the folic acid-binding protein one (Folbp1) gene display multiple developmental abnormalities, including neural and craniofacial defects. To better understand potential interactions between Folbp1 gene and selected genes involved in neural and craniofacial morphogenesis, we evaluated the expression patterns of a panel of crucial differentiation markers (Pax-3, En-2, Hox-a1, Shh, Bmp-4, Wnt-1, and Pax-1).
Methods: Folbp1 mice were supplemented with low dosages of folinic add to rescue nullizygotes from dying in utero before gestational day 10. The gene marker analyses were carried out by in situ hybridization.
Results: In nullizygote embryos with open cranial neural tube defects, the downregulation of Pax-3 and En-2 in the impaired midbrain, along with an observed upregulation of the ventralizing marker Shh in the expanded floor plate, suggested an important regulatory interaction among these three genes. Moreover, the nullizygotes also exhibit craniofacial abnormalities, such as cleft lip and palate. Pax-3 signals in the impaired medial nasal primordia were significantly increased, whereas Pax-1 showed no expression in the undeveloped lateral nasal processes. Although Shh was downregulated, Bmp-4 was strongly expressed in the medial and lateral nasal processes, highlighting the antagonistic activities of these molecules.
Conclusions: Impairment of Folbp1 gene function adversely impacts the expression of several critical signaling molecules. Mis-expression of these molecules, perhaps mediated by Shh, may potentially contribute to the observed failure of neural tube closure and the development of craniofacial defects in the mutant mice.