Brueckner Laboratory Research
Our Laboratory Research includes studies regarding:
- Cilia in Left-Right Development
- Cilia in Cardiac Development
- Genetic Control in Human Heterotoxy
- Left-Right Development
- Cardiac Development
- Human Heterotaxy
Cilia in Left-Right Development
The development of non-random asymmetry along the left-right axis is a unique feature of vertebrate development. Defects in this process in mouse and man commonly affect the development of the heart and result in severe congenital cardiac anomalies.Our goal is to understand the mechanism by which embryonic cilia create and signal left-right positional information, and to investigate whether cilia have essential roles in other developmental processes.
We have previously shown that the vertebrate LR axis is initiated at the mammalian node late in gastrulation. Dynein-driven motility of monocilia found on node cells generates directional flow of extraembryonic fluid, termed "nodal flow". The direction of nodal flow is determined by the inherent chirality of the cilium itself, and artificial reversal of nodal flow is able to reverse the LR axis. Nodal flow sets up an asymmetric calcium signal found in the cells at the left border of the node.
The development of LR asymmetry is also abnormal in mice with defects in the polycystin gene Pkd2, which functions in kidney monocilia as a mechanotransducer by mediating an intracellular calcium signal in response to fluid flow in the renal tubule. We have shown that Polycystin-2 protein localizes to a subset of node monocilia that are non-motile. This data suggests that embryonic cilia may be required to both create and sense nodal flow.
The major focus of our interest is: How is the asymmetric perinodal calcium signal transmitted to the developing organs to result in asymmetric morphogenesis?