BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo.
Deletion of various bone morphogenetic proteins (BMPs) and their downstream Smads in mice have clearly shown that BMP signaling is essential for the formation of primordial germ cells (PGCs). However, the molecular mechanism through which this takes place is still unclear. Here, we demonstrate that BMP4 produced in the extraembryonic ectoderm signals through ALK2, a type I BMP receptor, in the visceral endoderm (VE) to induce formation of PGCs from the epiblast. Firstly, embryonic day 5.5-6.0 (E5.5-E6.0) embryos cultured on fibronectin formed PGCs in the presence of VE, but not in its absence. Secondly, Alk2-deficient embryos completely lacked PGCs and the heterozygotes had reduced numbers, resembling Bmp4-deficient phenotypes. Thirdly, expression of constitutively active ALK2 in the VE, but not in the epiblast, was sufficient to rescue the PGC phenotype in Bmp4-deficient embryos. In addition, we show that the requirement for the VE at E5.5-E6.0 can be replaced by culturing embryos stripped of VE on STO cells, indicating that STO cells provide or transduce signals necessary for PGC formation that are normally transmitted by the VE. We propose a model in which direct signaling to proximal epiblast is supplemented by an obligatory indirect BMP-dependent signal via the VE.
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Susana M Chuva
SM
de Sousa Lopes
Bernard A J
BA
Roelen
Rui M
RM
Monteiro
Roul
R
Emmens
Herbert Y
HY
Lin
En
E
Li
Kirstie A
KA
Lawson
Christine L
CL
Mummery
D030201:Activin Receptors, Type I / Q000235:genetics / Q000502:physiology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology* / Q000502:physiology; D004707:Endoderm / Q000166:cytology / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000166:cytology / Q000502:physiology*; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D005353:Fibronectins; D011506:Proteins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse