Single cell multi-omic analysis identifies aTbx1-dependent multilineage primed population in the murine cardiopharyngeal mesoderm

Abstract

The poles of the heart and branchiomeric muscles of the face and neck are formed from the cardiopharyngeal mesoderm (CPM) within the pharyngeal apparatus. The formation of the cardiac outflow tract and branchiomeric muscles are disrupted in patients with 22q11.2 deletion syndrome (22q11.2DS), due to haploinsufficiency of TBX1, encoding a T-box transcription factor. Here, using single cell RNA-sequencing, we identified a multilineage primed population (MLP) within the CPM, marked by the Tbx1 lineage, which has bipotent properties to form cardiac and skeletal muscle cells. The MLPs are localized within the nascent mesoderm of the caudal lateral pharyngeal apparatus and provide a continuous source of progenitors that undergo TBX1-dependent progression towards maturation. Tbx1 also regulates the balance between MLP maintenance and maturation while restricting ectopic non-mesodermal gene expression. We further show that TBX1 confers this balance by direct regulation of MLP enriched genes and downstream pathways, partly through altering chromatin accessibility. Our study thus uncovers a new cell population and reveals novel mechanisms by which Tbx1 directs the development of the pharyngeal apparatus, which is profoundly altered in 22q11.2DS.

The cardiopharyngeal mesoderm contributes to lymphatic vessel development

“…Milgrom-Hoffman et al identified Flk1 + /Isl1 + endothelial populations in the second pharyngeal arch in mouse embryos from E7.5 to E9.5 37 . These cell populations may serve as progenitors for LECs and BECs in the cardiopharyngeal region through the sequential expression of Flk1, Tie2 , and/or Prox1 in response to different cues, leading to diverse fate determination, as revealed by recent single cell RNA-sequence analyses 38,39 .…”