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

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 f lagellar 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.

Cilia and Hedgehog responsiveness in the mouse

“…Other mutant strains used were Gli3 XT-J , an intragenic deletion allele (6); Ptch1 tm1Mps , a lacZ gene insertion allele (7); nodal tm1Rob , a lacZ gene insertion allele (8); and Kif3a tm1Maz , a targeted null allele (9). Mutant alleles were genotyped as described (3,(5)(6)(7)(8)(9).…”

Laterality defects are influenced by timing of treatments and animal model

“…Many treatments affecting LR asymmetry result in 20–40% heterotaxia, a much lower level than the 50–90% expected (depending on the number of organs assessed), an issue that is rarely if ever discussed [see for example (Nagai et al, 2010; Fogelgren et al, 2011; Marszalek et al, 1999; Bajoghli et al, 2007; Amack et al, 2007; Danilchik et al, 2006)]. A considerable number of studies on the mechanisms of LR asymmetry are available and comparable endpoints (i.e.…”

The radial spokes and central apparatus: Mechano‐chemical transducers that regulate flagellar motility

“…In addition, motility of naturally occurring central pairless cilia and flagella has been reported [Baccetti et al, 1979;Prensier et al, 1980;Nonaka et al, 1998]. Most notably, recent studies have demonstrated that the 9ϩ0 nodal cilia of developing embryos are motile, and this motility plays a critical role in establishing left-right asymmetry [Nonaka et al, 1998;Marszalek et al, 1999;Nonaka et al, 2002].…”