Left-right asymmetry and kinesin superfamily protein KIF3A:: New insights in determination of laterality and mesoderm induction by kif3A-/- mice analysis

KIF3A is a classical member of the kinesin superfamily proteins (KIFs), ubiquitously expressed although predominantly in neural tissues, and which forms a heterotrimeric KIF3 complex with KIF3B or KIF3C and an associated protein, KAP3,To elucidate the function of the kif3A gene in vivo, we made kif3A knockout mice. kif3A(-/-) embryos displayed severe developmental abnormalities characterized by neural tube degeneration and mesodermal and caudal dysgenesis and died during the midgestational period at similar to 10.5 dpc (daps post coitum), possibly resulting from cardiovascular insufficiency. Whole mount in situ hybridization of Pax6 revealed a normal pattern while staining by sonic hedgehog (shh) and Brachyury (T) exhibited abnormal patterns in the anterior-posterior (A-P) direction at both mesencephalic and thoracic levels. These results suggest that KIF3A might be involved in mesodermal patterning and in turn neurogenesis. Furthermore, homozygotes for kif3A showed randomization of laterality in heart looping. In contrast to wildtype embryos where almost all have a D-loop heart (situs solitas), similar to 40% of homozygous embryos exhibited cardiac L-loops (situs inversus). Moreover, their pericardial space was filled with effusion resulting from/in circulatory insufficiency. Scanning electron microscopy (SEM) and video-enhanced contrast DIC and fluorescent images (VECDIC/FL) microscopy revealed the absence of motile monocilia on mutant nodal pit cells, which could not generate leftward nodal flow of extraembryonic fluid and are considered to be responsible for initial determination of the left-right (L-R) asymmetry, These results collectively suggest the important role of the KIF3A protein in determination of embryonic body planning, particularly for the laterality.