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), ubi quitously expressed although predominantly in neural tissues, and which for ms a heterotrimeric KIF3 complex with KIF3B or KIF3C and an associated prot ein, KAP3,To elucidate the function of the kif3A gene in vivo, we made kif3 A knockout mice. kif3A(-/-) embryos displayed severe developmental abnormal ities characterized by neural tube degeneration and mesodermal and caudal d ysgenesis and died during the midgestational period at similar to 10.5 dpc (daps post coitum), possibly resulting from cardiovascular insufficiency. W hole mount in situ hybridization of Pax6 revealed a normal pattern while st aining by sonic hedgehog (shh) and Brachyury (T) exhibited abnormal pattern s in the anterior-posterior (A-P) direction at both mesencephalic and thora cic levels. These results suggest that KIF3A might be involved in mesoderma l patterning and in turn neurogenesis. Furthermore, homozygotes for kif3A s howed randomization of laterality in heart looping. In contrast to wildtype embryos where almost all have a D-loop heart (situs solitas), similar to 4 0% of homozygous embryos exhibited cardiac L-loops (situs inversus). Moreov er, their pericardial space was filled with effusion resulting from/in circ ulatory insufficiency. Scanning electron microscopy (SEM) and video-enhance d contrast DIC and fluorescent images (VECDIC/FL) microscopy revealed the a bsence of motile monocilia on mutant nodal pit cells, which could not gener ate leftward nodal flow of extraembryonic fluid and are considered to be re sponsible for initial determination of the left-right (L-R) asymmetry, Thes e results collectively suggest the important role of the KIF3A protein in d etermination of embryonic body planning, particularly for the laterality.