AUTHOR=Sauer Stephan , Klar Amar J.

TITLE=Left-right symmetry breaking in mice by left-right dynein may occur via a biased chromatid segregation mechanism, without directly involving the Nodal gene

JOURNAL=Frontiers in Oncology

VOLUME=2

YEAR=2012

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2012.00166

DOI=10.3389/fonc.2012.00166

ISSN=2234-943X

ABSTRACT=<p>Ever since cloning the classic <italic>iv</italic> (<italic><underline>i</underline>nversed</italic><italic><underline>v</underline>iscerum</italic>) mutation identified the “<italic>left-right dynein</italic>” (<italic>lrd</italic>) gene in mice, most research on body laterality determination has focused on its function in motile cilia at the node embryonic organizer. This model is attractive, as it links chirality of cilia architecture to asymmetry development. However, <italic>lrd</italic> is also expressed in blastocysts and embryonic stem cells, where it was shown to bias the segregation of recombined sister chromatids away from each other in mitosis. These data suggested that <italic>lrd</italic> is part of a cellular mechanism that recognizes and selectively segregates sister chromatids based on their replication history: old “Watson” versus old “Crick” strands. We previously proposed that the mouse left-right axis is established via an asymmetric cell division prior to/or during gastrulation. In this model, left-right dynein selectively segregates epigenetically differentiated sister chromatids harboring a hypothetical “<italic>left-right axis development 1</italic>” (“<italic>lra1</italic>”) gene during the left-right axis establishing cell division. Here, asymmetry development would be ultimately governed by the chirality of the cytoskeleton and the DNA molecule. Our model predicts that randomization of chromatid segregation in <italic>lrd</italic> mutants should produce embryos with 25% situs solitus, 25% situs inversus, and 50% embryonic death due to heterotaxia and isomerism. Here we confirmed this prediction by using two distinct <italic>lrd</italic> mutant alleles. Other than <italic>lrd</italic>, thus far <italic>Nodal</italic> gene is the most upstream function implicated in visceral organs laterality determination. We next tested whether the <italic>Nodal</italic> gene constitutes the <italic>lra1</italic> gene hypothesized in the model by testing mutant’s effect on 50% embryonic lethality observed in <italic>lrd</italic> mutants. Since <italic>Nodal</italic> mutation did not suppress lethality, we conclude that <italic>Nodal</italic> is not equivalent to the <italic>lra1</italic> gene. In summary, we describe the origin of 50% lethality in <italic>lrd</italic> mutant mice not yet explained by any other laterality-generating hypothesis.</p>