Dr, Dominic Norris,
January the 23rd
Title
Cilia, flow and polcystins: telling left from right in the mouse
Abstract
While externally mirror symmetrical between left and right, vertebrates show clear leftright (L-R) asymmetry in the positioning and patterning of their internal organs and
vasculature. This L-R asymmetry is evolutionarily conserved, reflecting both its ancient
origin and physiological significance. In early embryos, while left and right are
mathematically evident, L-R symmetry must be broken reliably in every embryo
resulting in cells having a left or right sided identity. The initial breaking of symmetry
occurs when motile cilia in the embryonic node (a transient pit shaped structure) rotate
so as to drive a leftward fluid flow. This biophysical force, known as nodal flow, is itself
‘perceived’ in a cilia dependent manner. The mechanisms involved remains
controversial. In this talk I will discuss our work on the role of cilia and in particular two
polycystin proteins, Pkd1l1 and Pkd2; all are required for normal L-R patterning. I will
provide evidence that Pkd1l1 is a strong candidate to be the elusive sensor of flow,
showing that it acts downstream of flow but upstream of early gene expression
asymmetries. Furthermore, our genetic experiments have revealed a novel pathway
linking the generation and sensation of flow to the establishment of asymmetric gene
expression. Finally, I discuss a small extracellular domain of Pkd1l1 that is essential for
function and might be central to the mechanism of flow sensation.
Bio
During his PhD Dr, Dominic Norris (with Sohaila Rastan and Neil Brockdorff) studied
mouse genetics and I worked on X-chromosome inactivation, demonstrating that CpG
methylation was a generic characteristic of the inactive X. Later on he continued on to
study Xist, revealing a methylation based genetic imprint; the fourth gene for which such
an imprint was demonstrated. He did his postdoc in Harvard with Liz Robertson, where
he trained in developmental biology and making targeted genetic modifications. There
he studied the Nodal locus, mapping then systematically deleting the enhancers that
control its expression. Nodal shows left-right asymmetric expression and it was here
that he first became interested in left-right (L-R) determination. He then returned to the
UK to take up an MRC career development award at MRC Harwell, establishing a
genetic screen to look for novel L-R mutants as well as screening for novel asymmetric
gene expression. So far he has identified new cilia motility mutants, novel (and
informative) alleles of known loci such as Pkd2 and new loci. These mutants have
formed the basis for his subsequent work. Out of these screens they identified Pkd1l1
as a novel L-R determinant and he has been analyzing this in increasing depth over the
past few years.