IMPC:Characterisation of 4933427D14Rik, an Lhx1 regulated gene, and specification of the left-right body axis

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Externally humans, and other mammals, appear bilaterally symmetrical. However internally they display an invariant left-right asymmetry. For example, the heart is tilted towards the left while the liver is placed on the right side of the abdomen. How this asymmetry is established is of great interest, both biologically and medically. Defects in human left-right (L-R) pattern formation cause birth defects affecting the heart, vasculature, lungs and gastrointestinal tract that can be life threatening. To understand how these L-R axis defects develop, it is important to more fully understand the molecular and cellular mechanisms by which L-R patterning is established. Cilia are important cellular organelles that can have sensory or motile roles and are critical in setting up the L-R axis. Cilia resemble small hair-like projections on the surface membrane of the cell and inside the cilia is a microtubule-based cytoskeleton. Cilia originate from centrosomes, a cell organelle that serves as the main microtubule organising centre, and consists of a mother and a daughter centriole. The formation of cilia, termed ciliogenesis, initiates when the mother centriole docks at the membrane forming the basal body of the cilia and from which the microtubule cytoskeleton of the cilia extends. In early mammalian development, a transient and architecturally distinct structure, the node, is formed and is essential for establishing the L-R axis. Morphologically the node is formed of a pit of cells, with each cell possessing a motile cilium. Stereotyped rotation of the cilia generates a unidirectional flow of fluid across the node from right to left, leading to asymmetric expression of a handful of genes, including Nodal. Asymmetric Nodal signalling is essential for specifying the L-R body axis as perturbations in Nodal signalling can lead to defects in L-R axis patterning. Lhx1 is a homeobox domain transcription factor whose expression is dependent on Nodal signalling. Embryos lacking Lhx1 display, among a plethora of faults, defects in node morphogenesis and in correct L-R axis patterning. We have recently identified Lhx1 regulated genes through transcriptional profiling experiments, among which was a relatively uncharacterised gene 4933427D14Rik. Exploiting the IMPC resource, our work will establish the role 4933427D14Rik plays in early development in setting up the L-R axis. Preliminary studies suggest that 4933427D14Rik is a centriolar satellite protein that may function in both centriole duplication and ciliogenesis. Preliminary phenotyping of 4933427D14Rik mutant embryos revealed problems in embryonic development that can be attributed to defects in ciliogenesis and L-R establishment. Medically, the recent finding that 4933427D14Rik is mutated in a ciliopathy patient with oral-facial-digital syndrome (OFDS) highlights the importance of this gene. Hence, 4933427D14Rik may play a key role in setting up the L-R axis downstream of Lhx1/Nodal signalling and characterisation of this centriolar satellite protein will ultimately provide insight into the mechanism underlying OFDS and related human birth defects.