Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II

Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II

^*Division of Cellular and Molecular Medicine, ^†Department of Pharmacology, ^§Department of Medicine and Center for Molecular Genetics, and ^‡Howard Hughes Medical Institute, University of California, San Diego School of Medicine, La Jolla, CA

Edited by William B. Wood III, University of Colorado, Boulder, CO, and approved February 24, 1999 (received for review December 31, 1998)

Abstract

The embryonic cellular events that set the asymmetry of the genetic control circuit controlling left-right (L-R) axis determination in mammals are poorly understood. New insight into this problem was obtained by analyzing mouse mutants lacking the KIF3A motor subunit of the kinesin-II motor complex. Embryos lacking KIF3A die at 10 days postcoitum, exhibit randomized establishment of L-R asymmetry, and display numerous structural abnormalities. The earliest detectable abnormality in KIF3A mutant embryos is found at day 7.5, where scanning electron microscopy reveals loss of cilia ordinarily present on cells of the wild-type embryonic node, which is thought to play an important role in setting the initial L-R asymmetry. This cellular phenotype is observed before the earliest reported time of asymmetric expression of markers of the L-R signaling pathway. These observations demonstrate that the kinesin-based transport pathway needed for flagellar and ciliary morphogenesis is conserved from Chlamydomonas to mammals and support the view that embryonic cilia play a role in the earliest cellular determinative events establishing L-R asymmetry.

Footnotes

↵ ¶ To whom reprint requests should be addressed at: HHMI/CMM Room 334, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0683. e-mail: lgoldstein{at}ucsd.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
ABBREVIATIONS:

L-R,

left-right;

ES,

embryonic stem;

p.c.,

postcoitum