Developmental expression of BMP4/ALK3/SMAD5 signaling pathway in the mouse testis: a potential role of BMP4 in spermatogonia differentiation.
It is well established that the c-kit gene plays an essential role in the proliferation of differentiating spermatogonia in prepuberal mice. However, the mechanisms that regulate the onset of spermatogenesis, i.e. differentiation of spermatogonial stem cells and c-kit expression, are poorly understood. Here we identify a novel signal transduction system in mouse prepuberal testis regulating this developmental event, involving bone morphogenetic protein 4 (BMP4) and its transduction machinery. BMP4 is produced by Sertoli cells very early in the postnatal life and is successively down regulated in peri-puberal Sertoli cells. Its receptor Alk3 and the R-Smad Smad5 are specifically expressed both in proliferating primordial germ cells and in postnatal spermatogonia. BMP4 stimulation of cultured spermatogonia induces Smad4/5 nuclear translocation and the formation of a DNA-binding complex with the transcriptional coactivator p300/CBP. In vitro exposure of undifferentiated spermatogonia to BMP4 exerts both mitogenic and differentiative effects, inducing [3H]thymidine incorporation and Kit expression. As a result of the latter event, Kit-negative spermatogonia acquire sensitivity to Stem Cell Factor.
Pellegrini
Manuela
M
Dipartimento di Sanita' Pubblica e Biologia Cellulare, Sezione di Anatomia, Universita' di Roma Tor Vergata, Rome, Italy.
Grimaldi
Paola
P
Rossi
Pellegrino
P
Geremia
Raffaele
R
Dolci
Susanna
S
D000123:Acetyltransferases / Q000378:metabolism; D029404:Activin Receptors / Q000378:metabolism*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D051548:Histone Acetyltransferases; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D010750:Phosphoproteins / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012708:Sertoli Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D051901:Smad4 Protein; D051902:Smad5 Protein; D013091:Spermatogenesis / Q000502:physiology; D013093:Spermatogonia / Q000166:cytology / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D029404:Activin Receptors; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D010750:Phosphoproteins; D019009:Proto-Oncogene Proteins c-kit; D051901:Smad4 Protein; D051902:Smad5 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C490810:Smad4 protein, mouse; C497798:Smad5 protein, mouse; C020723:citrate-binding transport protein