Identification of Type I and Type II Serine/Threonine Kinase Receptors for Growth/Differentiation Factor-5

Nishitoh, Hideki; Ichijo, Hidenori; Kimura, Michio; Matsumoto, Tomoaki; Makishima, Fusao; Yamaguchi, Akira; Yamashita, Hidetoshi; Enomoto, Shoji; Miyazono, Kohei

doi:10.1074/jbc.271.35.21345

Cited by 304 publications

(223 citation statements)

References 55 publications

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“…The appendicular defects in Bmpr1b mutant mice resemble those seen in mice homozygous for the Gdf5 null mice (Gdf5 bp-j ). Since Gdf5 has been shown to play a critical role in cartilage formation and binds Bmpr1b with high affinity (Nishitoh et al, 1996); these findings suggest that Bmpr1b plays a non-redundant role in cartilage formation in vivo. BMP ligands may utilize multiple type I BMP receptors to mediate their signaling during cartilage and bone formation.…”

Section: Knockout Of Bmp Bmpr and Smad Genesmentioning

confidence: 96%

“…Both Bmp5 and Gdf5 genes are localized on chromosome 2 in mice and on chromosome 20 in humans (Storm et al, 1994). GDF5 has been shown to bind BMPR-IB specifically (Nishitoh et al, 1996) and null mutations in the Bmpr1b gene causes a similar skeletal phenotype as that observed in Gdf5 mutant mice (Yi et al, 2000). Heterozygous missense mutations in Bmpr1b gene in humans cause brachydactyly type A2 through a dominant-negative effect.…”

Section: Naturally Occurring Mutations In Bmps and Bmp Receptorsmentioning

confidence: 99%

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The BMP signaling and in vivo bone formation

Cao

Chen

2005

Gene

272

197

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Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor β(TGFβ) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smads 1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and their signaling molecules have shown that BMP signaling plays critical roles in bone and cartilage development and postnatal bone formation. BMP activities are regulated at different molecular levels. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue.

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Section: Knockout Of Bmp Bmpr and Smad Genesmentioning

confidence: 96%

Section: Naturally Occurring Mutations In Bmps and Bmp Receptorsmentioning

confidence: 99%

The BMP signaling and in vivo bone formation

Cao

Chen

2005

Gene

272

197

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“…GDF9 is capable of stimulating cumulus expansion in vitro (32), raising the possibility that this oocyte-specific ligand binds to BMPRIB in vivo. However, GDF9 is structurally divergent from ligands known to bind to BMPRIB, and folliculogenesis is blocked at an early stage in Gdf9Ϫ͞Ϫ mice (3,33,34), but not in BmprIB mutants. Moreover, GDF9 increases Cox2 mRNA levels in vitro, whereas we observe increased levels of Cox2 in the absence of signaling through BMPRIB.…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that BMPRIB regulates levels of expression of these ligands and͞or their receptor(s) in follicle cells. Other potential ligands for BMPRIB include BMPs 2, 4, and 7, which are expressed in thecal cells and are known to signal through BMPRIB in vitro (2,7,34,35). GDF5 is the most potent stimulator of signal transduction through BMPRIB known to date (34).…”

Section: Discussionmentioning

confidence: 99%

The type I BMP receptor BmprIB is essential for female reproductive function

LaPolt

Yoon

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

190

109

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Maintenance of female reproductive competence depends on the actions of several hormones and signaling factors. Recent reports suggest roles for bone morphogenetic proteins (BMPs) in early stages of folliculogenesis. A role for the type I BMP receptor BmprIB as a regulator of ovulation rates in sheep has been described recently, but little is known about the roles of BMP signaling pathways in other aspects of reproductive function. We report here that BMPRIB is essential for multiple aspects of female fertility. Mice deficient in BmprIB exhibit irregular estrous cycles and an impaired pseudopregnancy response. BmprIB mutants produce oocytes that can be fertilized in vitro, but defects in cumulus expansion prevent fertilization in vivo. This defect is associated with decreased levels of aromatase production in granulosa cells. Unexpectedly, levels of mRNA for cyclooxygenase 2, an enzyme required for cumulus expansion, are increased. BmprIB mutants also exhibit a failure in endometrial gland formation. The expression of BmprIB in uterine linings suggests that these defects are a direct consequence of loss of BMP signaling in this tissue. In summary, these studies demonstrate the importance of BMP signaling pathways for estrus cyclicity, estradiol biosynthesis, and cumulus cell expansion in vivo and reveal sites of action for BMP signaling pathways in reproductive tissues.

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“…BDA2 is caused by heterozygous mutations in BMPR1B (Lehmann et al, 2003) that are thought to confer dominant-negative properties to the resulting BMPR1B protein. Of interest, BDA2 has also been shown to be associated with dominant mutations in GDF5 (Seemann et al, 2005;Kjaer et al, 2006;Lehmann et al, 2006;Ploger et al, 2008), the ligand for BMPR1B (Nishitoh et al, 1996). These mutations result in a partial loss of function by specifically interfering with the binding of GDF5 to BMPR1B but not to its other receptor BMPR1A (Seemann et al, 2005;Ploger et al, 2008).…”

Section: Condensation Of the Digit Anlagenmentioning

confidence: 99%

Mechanisms of digit formation: Human malformation syndromes tell the story

Stricker

Mundlos

2011

Developmental Dynamics

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Identifying the genetic basis of human limb malformation disorders has been instrumental in improving our understanding of limb development. Abnormalities of the hands and/or feet include defects affecting patterning, establishment, elongation, and segmentation of cartilaginous condensations, as well as growth of the individual skeletal elements. While the phenotype of such malformations is highly diverse, the mutations identified to date cluster in genes implicated in a limited number of molecular pathways, namely hedgehog, Wnt, and bone morphogenetic protein. The latter pathway appears to function as a key molecular network regulating different phases of digit and joint development. Studies in animal models not only extended our insight into the pathogenesis of these conditions, but have also contributed to our understanding of the in vivo functions and interactions of these key players. This review is aimed at integrating the current understanding of human digit malformations into the increasing knowledge of the molecular mechanisms of digit development. Developmental Dynamics 240:990-1004,

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Identification of Type I and Type II Serine/Threonine Kinase Receptors for Growth/Differentiation Factor-5

Abstract: Growth/differentiation factor-5 (GDF-5

Cited by 304 publications

References 55 publications

The BMP signaling and in vivo bone formation

The BMP signaling and in vivo bone formation

The type I BMP receptor BmprIB is essential for female reproductive function

Mechanisms of digit formation: Human malformation syndromes tell the story

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