Abstract
Cardiovascular lineages develop together with kidney, smooth muscle, and limb connective tissue progenitors from the lateral plate mesoderm (LPM). How the LPM initially emerges and how its downstream fates are molecularly interconnected remain unknown. Here, we isolate a pan-LPM enhancer in the zebrafish-specific draculin (drl) gene that provides specific LPM reporter activity from early gastrulation. In toto live imaging and lineage tracing of drl-based reporters captures the dynamic LPM emergence as lineage-restricted mesendoderm field. The drl pan-LPM enhancer responds to the transcription factors EomesoderminA, FoxH1, and MixL1 that combined with Smad activity drive LPM emergence. We uncover specific activity of zebrafish-derived drl reporters in LPM-corresponding territories of several chordates including chicken, axolotl, lamprey, Ciona, and amphioxus, revealing a universal upstream LPM program. Altogether, our work provides a mechanistic framework for LPM emergence as defined progenitor field, possibly representing an ancient mesodermal cell state that predates the primordial vertebrate embryo.
Highlights
Cardiovascular lineages develop together with kidney, smooth muscle, and limb connective tissue progenitors from the lateral plate mesoderm (LPM)
To resolve the dynamics of LPM emergence in toto, we performed time course experiments using single-plane illumination microscopy (SPIM) (Fig. 1a–d) and panoramic projections (Fig. 1e–h) of reporter-transgenic zebrafish embryos based on the full-length 6.35 kb drl cis-regulatory region. drl:EGFP-expressing LPM precursors became detectable by early gastrula stages (50% epiboly) and continuously condensed along the embryo margin through the end of gastrulation (Fig. 1a, b, f, g; Supplementary Movies 1,2)
Lmo2:dsRED2 labels embryonic hematopoietic and vascular tissues, and its expression overlaps with medial drl:EGFP-expressing cells in the anterior LPM (ALPM) and posterior LPM (PLPM) (Fig. 1i). scl:EGFP co-expressed with drl:mCherry in the most medial PLPM domain and in a small ALPM population (Fig. 1j)
Summary
Cardiovascular lineages develop together with kidney, smooth muscle, and limb connective tissue progenitors from the lateral plate mesoderm (LPM). Several transcription factors including Hand1/2, Tbx[5], Osr[1], FoxF1, Prrx[1], Mesp[1], and Etv[2] are expressed in LPM territories and play overlapping roles in cell fate determination[2,3,5], albeit not always with an evolutionarily conserved function[6] It remains incompletely understood how the LPM arises from an initial mesendodermal population that goes on to form distinct endodermal and mesodermal progenitors. Cre/loxmediated genetic lineage analysis has established that early drl reporter expression in zebrafish labels the LPM progenitors forming cardiovascular, blood, kidney, intestinal smooth muscles (iSMCs), and pectoral fin mesenchyme fates[14,15,16]. While drl as putative multimer zinc-finger gene has no obvious ortholog in other vertebrates[14,17,18], these observations suggest that the 6.35 kb drl region harbors cis-regulatory elements active throughout the prospective LPM starting from gastrulation, raising the possibility that these regulatory elements read out a pan-LPM program
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