TY - JOUR
T1 - Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives
AU - Freyer, Laina
AU - Hsu, Chih Wei
AU - Nowotschin, Sonja
AU - Pauli, Andrea
AU - Ishida, Junji
AU - Kuba, Keiji
AU - Fukamizu, Akiyoshi
AU - Schier, Alexander F.
AU - Hoodless, Pamela A.
AU - Dickinson, Mary E.
AU - Hadjantonakis, Anna Katerina
N1 - Funding Information:
We thank members of the Hadjantonakis lab and Nicolas Porchet for comments and suggestions on the manuscript; MSKCC’s Mouse Genetics Core Facility for production of germline transmitting chimeras; Rockefeller University’s Gene Targeting Facility for assistance in the generation of targeted embryonic stem cells (ESCs); the New York Genome Center for sequence data generation and analysis; and the Optical Imaging and Vital Microscopy core at BCM for microCT data. This work was supported by the National Institutes of Health ( F32GM115089 to L.F.; R01DK084391 and P30CA008748 to A.-K.H.; and U54HG006348 and R01HL128064 to M.E.D.) and the Natural Sciences and Engineering Research Council of Canada ( RGPIN418298-12 to P.A.H.). The Apela H2B-GFP ( Apela em1.1Hadj/J ) strain of mice is available from the Jackson Laboratory Mouse Mutant Resource as JAX Stock No.030845.
Publisher Copyright:
© 2017 The Author(s)
PY - 2017/8/29
Y1 - 2017/8/29
N2 - Apela (also known as Elabela, Ende, and Toddler) is a small signaling peptide that activates the G-protein-coupled receptor Aplnr to stimulate cell migration during zebrafish gastrulation. Here, using CRISPR/Cas9 to generate a null, reporter-expressing allele, we study the role of Apela in the developing mouse embryo. We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation. Three-dimensional micro-computed tomography revealed a higher penetrance of vascular remodeling defects, from which some mutants recover, and identified extraembryonic anomalies as the earliest morphological distinction in Apela mutant embryos. Transcriptomics at late gastrulation identified aberrant upregulation of erythroid and myeloid markers in mutant embryos prior to the appearance of physical malformations. Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin, leading to lethal cardiac defects in some Apela null embryos.
AB - Apela (also known as Elabela, Ende, and Toddler) is a small signaling peptide that activates the G-protein-coupled receptor Aplnr to stimulate cell migration during zebrafish gastrulation. Here, using CRISPR/Cas9 to generate a null, reporter-expressing allele, we study the role of Apela in the developing mouse embryo. We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation. Three-dimensional micro-computed tomography revealed a higher penetrance of vascular remodeling defects, from which some mutants recover, and identified extraembryonic anomalies as the earliest morphological distinction in Apela mutant embryos. Transcriptomics at late gastrulation identified aberrant upregulation of erythroid and myeloid markers in mutant embryos prior to the appearance of physical malformations. Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin, leading to lethal cardiac defects in some Apela null embryos.
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U2 - 10.1016/j.celrep.2017.08.014
DO - 10.1016/j.celrep.2017.08.014
M3 - Article
C2 - 28854362
AN - SCOPUS:85028422822
SN - 2211-1247
VL - 20
SP - 2116
EP - 2130
JO - Cell Reports
JF - Cell Reports
IS - 9
ER -