Transforming growth factor β receptor type 1 is essential for female reproductive tract integrity and function.
The transforming growth factor β (TGFβ) superfamily proteins are principle regulators of numerous biological functions. Although recent studies have gained tremendous insights into this growth factor family in female reproduction, the functions of the receptors in vivo remain poorly defined. TGFβ type 1 receptor (TGFBR1), also known as activin receptor-like kinase 5, is the major type 1 receptor for TGFβ ligands. Tgfbr1 null mice die embryonically, precluding functional characterization of TGFBR1 postnatally. To study TGFBR1-mediated signaling in female reproduction, we generated a mouse model with conditional knockout (cKO) of Tgfbr1 in the female reproductive tract using anti-Müllerian hormone receptor type 2 promoter-driven Cre recombinase. We found that Tgfbr1 cKO females are sterile. However, unlike its role in growth differentiation factor 9 (GDF9) signaling in vitro, TGFBR1 seems to be dispensable for GDF9 signaling in vivo. Strikingly, we discovered that the Tgfbr1 cKO females develop oviductal diverticula, which impair embryo development and transit of embryos to the uterus. Molecular analysis further demonstrated the dysregulation of several cell differentiation and migration genes (e.g., Krt12, Ace2, and MyoR) that are potentially associated with female reproductive tract development. Moreover, defective smooth muscle development was also revealed in the uteri of the Tgfbr1 cKO mice. Thus, TGFBR1 is required for female reproductive tract integrity and function, and disruption of TGFBR1-mediated signaling leads to catastrophic structural and functional consequences in the oviduct and uterus.
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
Qinglei
Q
Li
Julio E
JE
Agno
Mark A
MA
Edson
Ankur K
AK
Nagaraja
Takashi
T
Nagashima
Martin M
MM
Matzuk
D000818:Animals; D002478:Cells, Cultured; D004240:Diverticulum / Q000235:genetics / Q000473:pathology; D047108:Embryonic Development / Q000235:genetics*; D005187:Fallopian Tubes / Q000378:metabolism / Q000473:pathology; D005260:Female; D005298:Fertility / Q000235:genetics; D055429:Growth Differentiation Factor 9 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000254:growth & development* / Q000378:metabolism; D011374:Progesterone / Q000097:blood; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D055703:Reproductive Physiological Phenomena / Q000235:genetics*; D014599:Uterus / Q000002:abnormalities / Q000196:embryology*
C525898:Gdf9 protein, mouse; D055429:Growth Differentiation Factor 9; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor; D011374:Progesterone; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; C045073:Cre recombinase; D019426:Integrases