No turning,a Mouse Mutation Causing Left–Right and Axial Patterning Defects

Abstract

Patterning along the left/right axes helps establish the orientation of visceral organ asymmetries, a process which is of fundamental importance to the viability of an organism. A linkage between left/right and axial patterning is indicated by the finding that a number of genes involved in left/right patterning also play a role in anteroposterior and dorsoventral patterning. We have recovered a spontaneous mouse mutation causing left/right patterning defects together with defects in anteroposterior and dorsoventral patterning. This mutation is recessive lethal and was named no turning (nt) because the mutant embryos fail to undergo embryonic turning. nt embryos exhibit cranial neural tube closure defects and malformed somites and are caudally truncated. Development of the heart arrests at the looped heart tube stage, with cardiovascular defects indicated by ballooning of the pericardial sac and the pooling of blood in various regions of the embryo. Interestingly, in nt embryos, the direction of heart looping was randomized. Nodal and lefty, two genes that are normally expressed only in the left lateral plate mesoderm, show expression in the right and left lateral plate mesoderm. Lefty, which is normally also expressed in the floorplate, is not found in the prospective floor plate of nt embryos. This suggests the possibility of notochordal defects. This was confirmed by histological analysis and the examination of sonic hedgehog, Brachyury, and HNF-3 beta gene expression. These studies showed that the notochord is present in the early nt embryo, but degenerates as development progresses. Overall, these findings support the hypothesis that the notochord plays an active role in left/right patterning. Our results suggest that nt may participate in this process by modulating the notochordal expression of HNF-3 beta.

Nerve growth factor regulates axial rotation during early stages of chick embryo development

“…In chicken embryos, studies to investigate defects in axial rotation have not been previously reported and, consequently, the mechanisms responsible for this phenomenon are unknown. On the other hand, in the mouse embryo, defects characterized by a lack of rotation occur in the natural "no turning" mutant (25) and in experimentally induced genetic knockout mutants for the Csk (26,27), rotatin (28,29), and furin (30,31) genes. Real-time PCR shows that Csk mRNA expression is down-regulated 30 min after injection (Fig.…”

“…Fold changes (fc) are in linear scale: values for down-regulated genes (green) are in the interval 0.00 < fc < 1/1.25 and for up-regulated genes (red) fc > 1. 25. Ratio of fc of embryos injected with αD11 and 9E10 is in logarithmic scale.…”

Man1, an inner nuclear membrane protein, regulates left–right axis formation by controlling nodal signaling in a node‐independent manner

“…Among them, mutants for Lefty1 , Lefty2 , Nodal/Foxa2 (Collignon et al, 1996), Polaris (Murcia et al, 2000), Sil (Izraeli et al, 1999), Smad5 (Chang et al, 2000), Wnt3a (Nakaya et al, 2005), no turning (Melloy et al, 1998), Shh (Izraeli et al, 1999;Meyers and Martin, 1999;Tsukui et al, 1999), and Activin A receptor type I (AcvrI; Kishigami et al, 2004) show bilateral Nodal expression in the LPM. Because Lefty1 expression in the PFP is lost in these mutants, their phenotypes can be explained by the lack of Lefty1, which may allow the Nodal signal emanating from the left to the right LPM to cross the midline (Fig.…”

Cell death along the embryo midline regulates left–right sidedness

“…The notochord itself is known to be important for maintaining the position of the midline and in the asymmetric orientation of the organs during embryogenesis (Danos and Yost, 1996;Lohr et al, 1997;Melloy et al, 1998;Rebagliati et al, 1998;Sampath et al, 1998;Izraeli et al, 1999). Little is known about the mechanism that triggers the asymmetric expression of laterality genes.…”