Abstract
ABSTRACTThe Tbx6 transcription factor plays multiple roles during gastrulation, somite formation and body axis determination. One of the notable features of the Tbx6 homozygous mutant phenotype is randomization of left/right axis determination. Cilia of the node are morphologically abnormal, leading to the hypothesis that disrupted nodal flow is the cause of the laterality defect. However, Tbx6 is expressed around but not in the node, leading to uncertainty as to the mechanism of this effect. In this study, we have examined the molecular characteristics of the node and the genetic cascade determining left/right axis determination. We found evidence that a leftward nodal flow is generated in Tbx6 homozygous mutants despite the cilia defect, establishing the initial asymmetric gene expression in Dand5 around the node, but that the transduction of the signal from the node to the left lateral plate mesoderm is disrupted due to lack of expression of the Nodal coligand Gdf1 around the node. Gdf1 was shown to be a downstream target of Tbx6 and a Gdf1 transgene partially rescues the laterality defect.
Highlights
The bilateral symmetry of the early mouse embryo is broken during early gastrulation when genes are asymmetrically expressed around the embryonic node and in the lateral plate mesoderm (LPM)
We have examined the molecular characteristics of the node and the genetic cascade determining left/right axis determination
We found evidence that a leftward nodal flow is generated in Tbx6 homozygous mutants despite the cilia defect, establishing the initial asymmetric gene expression in Dand5 around the node, but that the transduction of the signal from the node to the left lateral plate mesoderm is disrupted due to lack of expression of the Nodal coligand Gdf1 around the node
Summary
The bilateral symmetry of the early mouse embryo is broken during early gastrulation when genes are asymmetrically expressed around the embryonic node and in the lateral plate mesoderm (LPM). The initial asymmetric gene expression around the node is driven by the motility of the monocilia on cells of the node, which creates a leftward flow of extracellular fluid. This flow is sensed by the cilia of the crown cells on the left side of the node through a mechanism involving the ion channel gene Pkd, initiating a cascade of asymmetric gene expression (Babu and Roy, 2013; Delling et al, 2016; Norris, 2012). Nodal signal spreads to the left LPM where it induces its own expression and that of other asymmetric genes such as Pitx (Norris, 2012). Homozygous null mutants for either Nodal or Gdf show a loss of expression of left-specific genes in the LPM (Rankin et al, 2000; Saijoh et al, 2003)
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