title: Loss of smad4 in Sertoli and Leydig cells leads to testicular dysgenesis and hemorrhagic tumor formation in mice.
abstract: As the central component of canonical TGFbeta superfamily signaling, SMAD4 is a critical regulator of organ development, patterning, tumorigenesis, and many other biological processes. Because numerous TGFbeta superfamily ligands are expressed in developing testes, there may exist specific requirements for SMAD4 in individual testicular cell types. Previously, we reported that expansion of the fetal testis cords requires expression of SMAD4 by the Sertoli cell lineage. To further uncover the role of Smad4 in murine testes, we produced conditional knockout mice lacking Smad4 in either Leydig cells or in both Sertoli and Leydig cells simultaneously. Loss of Smad4 concomitantly in Sertoli and Leydig cells led to underdevelopment of the testis cords during fetal life and mild testicular dysgenesis in young adulthood (decreased testis size, partially dysgenic seminiferous tubules, and low sperm production). When the Sertoli/Leydig cell Smad4 conditional knockout mice aged (56- to 62-wk old), the testis phenotypes became exacerbated with the appearance of hemorrhagic tumors, Leydig cell adenomas, and a complete loss of spermatogenesis. In contrast, loss of Smad4 in Leydig cells alone did not appreciably alter fetal and adult testis development. Our findings support a cell type-specific requirement of Smad4 in testis development and suppression of testicular tumors.
authors: Department of Comparative Biosciences, University of Illinois, Urbana, Illinois.
authors: Denise R
authors: DR
authors: Archambeault
authors: Humphrey Hung-Chang
authors: HH
authors: Yao
mesh_terms: D000236:Adenoma / Q000473:pathology; D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D006059:Gonadal Dysgenesis / Q000235:genetics* / Q000473:pathology*; D006470:Hemorrhage / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D007150:Immunohistochemistry; D007985:Leydig Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D012671:Seminiferous Tubules / Q000187:drug effects / Q000502:physiology; D012708:Sertoli Cells / Q000502:physiology*; D051901:Smad4 Protein / Q000235:genetics* / Q000502:physiology*; D013736:Testicular Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D013737:Testis / Q000254:growth & development / Q000502:physiology
chemical_list: D051901:Smad4 Protein; C490810:Smad4 protein, mouse
keywords: Leydig cell hyperplasia; Smad; azoospermia; hemorrhage; mouse; teratoma; testicular dysgenesis; testis