Open AccessPbx4 limits heart size and fosters arch artery formation through partitioning second heart field progenitors and restricting proliferation
Author(s) -
Andrew Holowiecki,
Kelsey Linstrum,
Padmapriyadarshini Ravisankar,
Kashish Chetal,
Nathan Salomonis,
Joshua S. Waxman
Publication year - 2020
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.15
H-Index - 36
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.185652
Subject(s) - biology , progenitor cell , progenitor , zebrafish , microbiology and biotechnology , heart development , anatomy , transcription factor , homeotic gene , cellular differentiation , immunology , stem cell , genetics , embryonic stem cell , gene
Vertebrate heart development requires the integration of temporally-distinct differentiating progenitors. However, few signals are understood that restrict the size of the later-differentiating outflow tract (OFT). We show that improper specification and proliferation of second heart field (SHF) progenitors in zebrafish lazarus (lzr) mutants, which lack the transcription factor Pbx4, produces enlarged hearts due to an increase in ventricular and smooth muscle cells. Specifically, Pbx4 initially promotes the partitioning of the SHF into anterior progenitors, which contribute to the OFT, and adjacent endothelial cell progenitors, which contribute to posterior pharyngeal arches. Subsequently, Pbx4 limits SHF progenitor (SHFP) proliferation. Single-cell RNA sequencing of nkx2.5+ cells revealed previously unappreciated distinct differentiation states and progenitor subpopulations that normally reside within the SHF and arterial pole of the heart. Specifically, Pbx4-deficient nkx2.5+ SHFPs have less distinct transcriptional profiles and display characteristics of normally discrete proliferative progenitor and anterior, differentiated cardiomyocyte populations. Therefore, our data indicate that the generation of proper OFT size and arch arteries requires Pbx-dependent stratification of unique differentiation states to facilitate both homeotic-like transformations and limit progenitor production within the SHF.