p38 (Mapk14/11) occupies a regulatory node governing entry into primitive endoderm differentiation during preimplantation mouse embryo development.
During mouse preimplantation embryo development, the classically described second cell-fate decision involves the specification and segregation, in blastocyst inner cell mass (ICM), of primitive endoderm (PrE) from pluripotent epiblast (EPI). The active role of fibroblast growth factor (Fgf) signalling during PrE differentiation, particularly in the context of Erk1/2 pathway activation, is well described. However, we report that p38 family mitogen-activated protein kinases (namely p38α/Mapk14 and p38β/Mapk11; referred to as p38-Mapk14/11) also participate in PrE formation. Specifically, functional p38-Mapk14/11 are required, during early-blastocyst maturation, to assist uncommitted ICM cells, expressing both EPI and earlier PrE markers, to fully commit to PrE differentiation. Moreover, functional activation of p38-Mapk14/11 is, as reported for Erk1/2, under the control of Fgf-receptor signalling, plus active Tak1 kinase (involved in non-canonical bone morphogenetic protein (Bmp)-receptor-mediated PrE differentiation). However, we demonstrate that the critical window of p38-Mapk14/11 activation precedes the E3.75 timepoint (defined by the initiation of the classical 'salt and pepper' expression pattern of mutually exclusive EPI and PrE markers), whereas appropriate lineage maturation is still achievable when Erk1/2 activity (via Mek1/2 inhibition) is limited to a period after E3.75. We propose that active p38-Mapk14/11 act as enablers, and Erk1/2 as drivers, of PrE differentiation during ICM lineage specification and segregation.
Laboratory of Developmental Biology and Genetics (LDB&G), Department of Molecular Biology, Faculty of Science, University of South Bohemia, Branišovská 31, 37005 České Budějovice, Czech Republic.
Vasanth
V
Thamodaran
Laboratory of Developmental Biology and Genetics (LDB&G), Department of Molecular Biology, Faculty of Science, University of South Bohemia, Branišovská 31, 37005 České Budějovice, Czech Republic Biology Centre of the Czech Academy of Sciences, Institute of Entomology, Branišovská 31, 37005 České Budějovice, Czech Republic awbruce@prf.jcu.cz.
Alexander W
0000-0003-4297-4412
AW
Bruce
D000818:Animals; D001755:Blastocyst / Q000502:physiology*; D002454:Cell Differentiation; D047108:Embryonic Development; D004707:Endoderm / Q000196:embryology*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005855:Germ Layers / Q000502:physiology; D051379:Mice; D048290:Mitogen-Activated Protein Kinase 11 / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
D012333:RNA, Messenger; D005346:Fibroblast Growth Factors; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14
cell signalling; cell-fate; mitogen-activated protein kinase; p38α/p38β Mapk14/Mapk11; preimplantation mouse embryo; primitive endoderm