BMP activities
are modulated not only through gene expression and protein processing, but also by interaction with antagonists such as
Noggin and Chordin (603475). Excess BMP activity in the Noggin-null mutant mouse results in excess cartilage and failure
to initiate joint formation. Murine Noggin is expressed in condensing cartilage and immature chondrocytes, as are many
BMPs. The excess BMP activity in the absence of Noggin antagonism may enhance the recruitment of cells into cartilage,
resulting in oversized growth plates. Chondrocytes are also refractory to joint-inducing positional cues. The Noggin gene
was first discovered as an important factor in brain and nerve development. Knockout mice have stubby, continuous limbs
with lack of joints in the paws, along with a fatal array of other developmental defects. The gene earned its name when, in
connection with studies of its role in the brain and nervous system, it was found that frog embryos injected with its mRNA
grew exceptionally large heads. In the developing frog, the Noggin protein also mimics the activity of the Spemann
organizer, which can make dorsal tissue out of ventral tissue. The secreted polypeptide Noggin (encoded by the NOG gene) binds and inactivates members of the transforming growth
factor-beta superfamily signaling proteins, such as bone morphogenetic protein-4 (BMP4; 112262). By diffusing through
extracellular matrices more efficiently than members of the TGF-beta superfamily, Noggin may have a principal role in
creating morphogenic gradients.
NCBI Summary:
The secreted polypeptide, encoded by this gene, binds and inactivates members of the transforming growth factor-beta (TGF-beta) superfamily signaling proteins, such as bone morphogenetic protein-4 (BMP4). By diffusing through extracellular matrices more efficiently than members of the TGF-beta superfamily, this protein may have a principal role in creating morphogenic gradients. The protein appears to have pleiotropic effect, both early in development as well as in later stages. It was originally isolated from Xenopus based on its ability to restore normal dorsal-ventral body axis in embryos that had been artificially ventralized by UV treatment. The results of the mouse knockout of the ortholog suggest that it is involved in numerous developmental processes, such as neural tube fusion and joint formation. Recently, several dominant human NOG mutations in unrelated families with proximal symphalangism (SYM1) and multiple synostoses syndrome (SYNS1) were identified; both SYM1 and SYNS1 have multiple joint fusion as their principal feature, and map to the same region (17q22) as this gene. All of these mutations altered evolutionarily conserved amino acid residues. The amino acid sequence of this human gene is highly homologous to that of Xenopus, rat and mouse. [provided by RefSeq, Jul 2008]
General function
Extracellular binding protein
Comment
Cellular localization
Secreted
Comment
Ovarian function
Steroid metabolism, Oogenesis, Early embryo development
Comment
Effects of bone morphogenic protein 4 (BMP4) and its inhibitor, Noggin, on in vitro maturation and culture of bovine preimplantation embryos. La Rosa I et al. ABSTRACT: BACKGROUND: BMP4 is a member of the transforming growth factor beta (TGFbeta) superfamily and Noggin is a potent BMP inhibitor that exerts its function by binding to BMPs preventing interactions with its receptors. The aim of this work was to investigate the role of BMP4 and Noggin, on oocytes in vitro maturation (m experiments) and embryos in vitro development (c experiments) of bovine. METHODS: For m experiments, COCs were collected from slaughterhouse ovaries and in vitro matured in TCM with 100 ng/ml of either BMP4 or Noggin. After 24 h, the nuclear stage of the oocytes was determined by staining with Hoechst 33342. In addition, RT- qPCR was performed on MII oocytes to study the relative concentration of ZAR1, GDF9, BAX, MATER and HSP70 transcripts. Treated oocytes were submitted to parthenogenic activation (PA) or in vitro fertilization (IVF) and cultured in CR2. For c experiments, non- treated matured oocytes were submitted to PA or IVF to generate embryos that were exposed to 100 ng/ml of BMP4 or Noggin in CR2 until day nine of culture. Cleavage, blastocyst and hatching rates, expression pattern of the transcription factor Oct-4 in blastocysts and embryo cell number at day two and nine post-activation or fertilization were evaluated. RESULTS: We found that Noggin, as BMP4, did not affect oocyte nuclear maturation.Noggin supplementation up- regulated the expression of HSP70 and MATER genes in matured oocytes. Moreover, BMP4 during maturation increased the proportion of Oct-4 positive cells in parthenogenic embryos. On the other hand, when Noggin was added to embryo culture medium, developmental rates of parthenogenic and in vitro fertilized embryos were reduced. However, BMP4 addition decreases the development only for in vitro fertilized embryos. BMP4 and Noggin during culture reduced the proportion of Oct-4- expressing cells. CONCLUSIONS: Our results show that BMP4 is implicated in bovine oocytes maturation and embryo development. Moreover, our findings demonstrate, for the first time, that a correct balance of BMP signaling is needed for proper pre-implantation development of bovine embryos.
Smith WC, Harland RM. 1992 reported the expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos.
They have cloned a cDNA encoding a novel polypeptide capable of inducing dorsal development in Xenopus embryos. RNA transcripts from this clone rescue normal development when injected into ventralized embryos and result in excessive head development at high doses. They have named the cDNA noggin, noggin cDNA contains a single reading frame encoding a 26 kd protein with a hydrophobic amino-terminal sequence, suggesting that it is secreted. In Northern blot analysis this cDNA hybridizes to two mRNAs that are expressed both maternally and zygotically. Although noggin transcript is not localized in the oocyte and cleavage stage embryo, zygotic transcripts are initially restricted to the presumptive dorsal mesoderm and reach their highest levels at the gastrula stage in the dorsal lip of the blastopore (Spemann organizer). In the neurula, noggin is transcribed in the notochord and prechordal mesoderm. The activity of exogenous noggin RNA in embryonic axis induction and the localized expression of endogenous noggin transcripts suggest that noggin plays a role in normal dorsal development.
A Novel Antagonistic Effect of the Bone Morphogenetic Protein System on Prolactin Actions in Regulating Steroidogenesis by Granulosa Cells. Nakamura E et al. To investigate the mechanism by which prolactin (PRL) regulates follicular steroidogenesis in the ovary, we examined the functional roles of PRL in steroidogenesis using rat oocyte/granulosa cell coculture and focusing on the bone morphogenetic protein (BMP) system. The expression of long and short forms of PRL receptor (PRLR) were detected in both oocytes and granulosa cells, and PRL effectively up-regulated PRLR expression in granulosa cells in the presence of FSH. PRL suppressed FSH-induced estradiol production and increased FSH-induced progesterone production in granulosa cells. The PRL effects on FSH-induced progesterone were blocked by coculture with oocytes, implying roles of oocyte-derived factors in suppression of progesterone production in PRL-exposed granulosa cells. In accordance with the data for steroids, FSH-induced aromatase expression was suppressed by PRL, whereas FSH-induced steroidogenic acute regulatory protein, P450scc (P450 side-chain cleavage enzyme), and 3beta-hydroxysteroid dehydrogenase type 2 levels were amplified by PRL. However, forskolin- and N(6),O(2)-dibutyryl cAMP-induced steroid levels and FSH- and forskolin-induced cAMP were not affected by PRL, suggesting that PRL action on FSH-induced steroidogenesis was not due to cAMP-protein kinase A regulation. Treatment with a BMP-binding protein, noggin, facilitated PRL-induced estradiol reduction, and noggin increased PRL-induced progesterone production in FSH-treated granulosa cells cocultured with oocytes, suggesting that endogenous BMPs reduce progesterone but increase estradiol when exposed to high concentrations of PRL. PRL increased the expression of BMP ligands in oocyte/granulosa cell coculture and augmented BMP-induced phosphorylated mothers against decapentaplegic 1/5/8 signaling by reducing inhibitory phosphorylated mothers against decapentaplegic 6 expression through the Janus kinase/signal transducer and activator of transcription (STAT) pathway. In addition to STAT activation, PRL enhanced FSH-induced MAPK phosphorylation in granulosa cells, in which ERK activation was preferentially involved in suppression of FSH-induced estradiol. Furthermore, noggin treatment enhanced PRLR signaling including MAPK and STAT. Considering that BMPs suppressed PRLR in granulosa cells, it is likely that the BMP system in growing follicles plays a key role in antagonizing PRLR signaling actions in the ovary exposed to high concentrations of PRL.
Expression regulated by
Comment
Ovarian localization
Oocyte, Granulosa
Comment
Follicle stages
Preovulatory
Comment
Phenotypes
POF (premature ovarian failure)
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: embryonic lethal Comment: During mouse embryogenesis, Nog is expressed at multiple sites, including developing
bones. Nog -/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton (McMahon et
al., 1998;Brunet et al., 1998 ).
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Premature ovarian failure in a female with proximal symphalangism and Noggin mutation.
Kosaki K, et al .
OBJECTIVE: To report a case of premature ovarian failure (POF) and a mutation of the gene for Noggin (NOG). DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 33-year-old Japanese female with POF and proximal symphalangism. INTERVENTION(S): Direct sequence analysis of the NOG gene. MAIN OUTCOME MEASURE(S): Occurrence of POF. RESULT(S): A novel heterozygous G to A transition was identified at the nucleotide position 142 (142 G>A), which is predicted to cause an amino acid substitution of glutamic acid by lysine (E48K). CONCLUSION(S): Because NOG is expressed in the ovary and interacts with bone morphogenetic proteins, which play an important role in the ovarian function, a NOG mutation may constitute one of the multiple susceptibility genes for the development of POF.