Study of the role of the Ofd1 protein in the hippocampus

The Oral-facial-digital type 1 syndrome (OFD1, MIM 311200) is a developmental disorder that belongs to a heterogeneous group of cilipathies. OFD1 is transmitted as an X-linked dominant condition with male embryonic lethality. The females, however, have abnormalities affecting the face, the oral cavity and the skeletal structures. The OFD1 gene, responsible for the disease, codifies for the OFD1 protein, localized in the basal body of the primary cilium and in centrosome. During embryonic development OFD1 is essential in the process of ciliogenesis and left-right axis specification. The primary cilium is crucial in Hedgehog signal transduction pathway, essential in the organization of the nervous system. Few OFD1 cases display mental retardation that is not associated with structural abnormalities of the CNS and this suggests that the primary cilium might have role in maintaining brain function. We know that Ofd1 is expressed in Mus musculus hippocampus, cerebellum and olfactory bulbs. In order to evaluate the role of Ofd1 in cerebral functions we used as a model organism transgenic mice in which the Ofd1 gene was conditionally inactivated in the hippocampus from day P21. A month after birth, hippocampi showed no morphological alterations in their organization. The images obtained at CLSM showed the presence of the primary cilium that has, in particular at the level of the cells of the dentate gyrus, reduced size in KO compared to wt. It was observed by TEM in KO samples the presence of prociglia both in the cells of the dentate gyrus and of the CA1 region with the presence of alterations in the microtubular basal body organization. These preliminary data confirm that the presence of Ofd1 is essential for maintaining the primary cilium that is altered due to the onset of neurological defects present in OFD1.