Members of the bone morphogenetic protein (BMP) family play diverse roles in multiple developmental processes. However, in the mouse, mutations in many BMPs, BMP receptors and signaling components result in early embryonic lethality making it difficult to analyze the role of these factors during organogenesis or tissue homeostasis in the adult. To bypass this early lethality, we used an organ culture system to study the role of BMPs during primordial germ cell (PGC) migration. PGCs are the embryonic precursors of the sperm and eggs. BMPs induce formation of primordial germ cells within the proximal epiblast of embryonic day 7.5 (E7.5) mouse embryos. PGCs then migrate via the gut to arrive at the developing gonads by E10.5. Addition of BMP4 or the BMP-antagonist Noggin to transverse slices dissected from E9.5 embryos elevated PGC numbers or reduced PGC numbers, respectively. Noggin treatment also slowed and randomized PGC movements, resulting in a failure of PGCs to colonize the urogenital ridges (UGRs). Based on p-Smad1/5/8 staining, migratory PGCs do not respond to endogenous BMPs. Instead, the somatic cells of the urogenital ridges exhibit elevated p-Smad1/5/8 staining revealing active BMP signaling within the UGRs. Noggin treatment abrogated p-Smad staining within the UGRs and blocked localized expression of Kitl, a cytokine known to regulate the survival and motility of PGCs and Id1, a transcription factor expressed within the UGRs. We propose that BMP signaling regulates PGC migration by controlling gene expression within the somatic cells along the migration route and within the genital ridges.
Stem cells are necessary to maintain tissue homeostasis and the microenvironment (a.k.a. the niche) surrounding these cells controls their ability to self renew or differentiate. For many stem cell populations it remains unclear precisely what cells and signals comprise a niche. Here we identify a possible PGC niche in the mouse genital ridges. Conditional ablation of Bmpr1a was used to demonstrate that BMP signaling is required for PGC survival and migration as these cells colonize the genital ridges. Reduced BMP signaling within the genital ridges led to increased somatic cell death within the mesonephric mesenchyme. Loss of these supporting cells correlated with decreased levels of the mesonephric marker, Pax2, as well as a reduction in genes expressed in the coelomic epithelium including the putative PGC chemo-attractants Kitl and Sdf1a. We propose that BMP signaling promotes mesonephric cell survival within the genital ridges and that these cells support correct development of the coelomic epithelium, the target of PGC migration. Loss of BMP signaling leads to the loss of the PGC target resulting in reduced PGC numbers and disrupted PGC migration.
Background: Primordial germ cells (PGCs) are the embryonic precursors of the sperm and eggs. Environmental or genetic defects that alter PGC development can impair fertility or cause formation of germ cell tumors.
A stem cell niche is a specialized tissue environment that controls the proliferation and differentiation of its resident stem cells. The functions of these structures have been well characterized in adult organisms. In particular, the bone marrow stem cell niche in mammals has been amenable to analysis because of the ability of transplanted hematopoietic cells to home and to recolonize the bone marrow of an irradiated host. Despite clues from adult models, it remains unclear how stem cells become partitioned into appropriate niches during embryonic development. To examine the earliest steps in niche formation, we created an organ culture system to observe the development of primordial germ cells (PGCs), a migratory stem cell population that will eventually give rise to the gametes. Using this assay, we can watch PGCs as they migrate to colonize the developing gonads and can introduce growth factor agonists or antagonists to test the function of proteins that regulate this process. This provides an unprecedented opportunity to identify the cellular and molecular interactions required for the formation of the germ cell niche.
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