Decoding cardiovascular lineage origins in space and time
Dr Christian MOSIMANN
Institute of Molecular Life Sciences, University of Zürich, Switzerland
Thursday, December 13th 2018 - 3 p.m.
- Meeting room 1005, IGBMC
Hosted by Julien VERMOT
The formation of multilineage progenitor cells is fundamental to the patterning of the vertebrate embryo. Cardiovascular progenitors arise along with kidney, smooth muscle, and limb skeleton lineages from lateral plate mesoderm (LPM). How the LPM is initially specified and what molecular mechanisms guide its peculiar collection of multilineage progenitors remain unknown. We study LPM formation and patterning using advanced transgenic approaches, genome editing, cross-species comparisons, and in toto imaging in the zebrafish (Danio rerio)
Using the first pan-LPM reporters based in the zebrafish drl gene, we charted the emergence of the LPM from a dedicated mesendoderm field. Cross-species reporter assays further revealed that drl reporter activity maps to LPM-corresponding territories in embryos of several chordate species, revealing an evolutionarily conserved LPM program. Towards deciphering the patterning of the cardiovascular system within the LPM, live imaging of reporters based on the zebrafish tbx1 locus documented the continuous formation of the zebrafish heart ventricle from a bilateral cardiopharyngeal progenitor field. Harnessing our transgenic readouts for establishing genotype-phenotype correlations, we apply maximized CRISPR-Cas9 mutagenesis for rapid loss-of-function testing of genes and cis-regulatory elements. Now, we are combining gene-regulatory analysis, single-cell trancriptomics, and lineage analysis to understand the fundamental partitioning of the LPM cell fates.
Altogether, our work establishes the LPM as paradigm for developmental cell fate determination from multilineage progenitors and as basis to unravel the causes of congenital cardiovascular defects.