Developmental Signals - TGF-beta

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Transforming Growth Factor-beta (TGF-beta, TGF-β) this is a superfamily signaling pathway with many different roles during development. Anti-Müllerian hormone (AMH) is also a member of the Transforming Growth Factor-β family of secreted signaling proteins.

TGF-beta signaling pathway[1]

TGF Members: AMH

Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular

Some Recent Findings

  • Review - TGF-β Family Signaling in Early Vertebrate Development[2] "TGF-β family ligands function in inducing and patterning many tissues of the early vertebrate embryonic body plan. Nodal signaling is essential for the specification of mesendodermal tissues and the concurrent cellular movements of gastrulation. Bone morphogenetic protein (BMP) signaling patterns tissues along the dorsal-ventral axis and simultaneously directs the cell movements of convergence and extension. After gastrulation, a second wave of Nodal signaling breaks the symmetry between the left and right sides of the embryo. During these processes, elaborate regulatory feedback between TGF-β ligands and their antagonists direct the proper specification and patterning of embryonic tissues. In this review, we summarize the current knowledge of the function and regulation of TGF-β family signaling in these processes. Although we cover principles that are involved in the development of all vertebrate embryos, we focus specifically on three popular model organisms: the mouse Mus musculus, the African clawed frog of the genus Xenopus, and the zebrafish Danio rerio, highlighting the similarities and differences between these species."
  • Prenatal nicotine exposure increases osteoarthritis susceptibility in male elderly offspring rats via low-function programming of the TGFβ signaling pathway[3] "Epidemiological investigations indicate that effects related to prenatal adverse environments on the organs of the offspring could continue to adulthood. This study intends to confirm that prenatal nicotine exposure (PNE) increases the susceptibility of osteoarthritis (OA) in the male offspring, and to explore the potential intrauterine programming mechanism. During pregnancy, rats were divided into a PNE group and a control group. After birth, rats were given a high-fat diet for 6 months and long-distance running for 6 weeks. The rats were euthanized at 18 months after birth (PM18) and on gestational day 20 (GD20), respectively. Knee joints were collected for histochemistry, immunohistochemistry, and quantitative polymerase chain reaction (qPCR) assays. Histological analyses and the Mankin's score showed increased cartilage destruction and accelerated OA progression in adult offspring from the PNE group. Immunohistochemistry results showed decreased expression of transforming growth factor beta (TGFβ) signaling pathway. Furthermore, the expression of apoptosis factors (caspase-3 and caspase-8), inflammatory factors [interleukin (IL)-1, IL-6] and matrix degradation enzymes [matrix metalloproteinase (MMP)-3, MMP-13] were also significantly increased. Traced back to the intrauterine period, it was found that the number of chondrocytes and the contents of Col2A1 and aggrecan in the matrix in the PNE group were decreased. And, the expression of the TGFβ signaling pathway was inhibited. These results suggested that PNE enhanced the susceptibility of OA in male elderly offspring rats by down-regulating TGFβ signaling, which increased articular cartilage local inflammation, matrix degradation, and cell apoptosis. This study confirmed the developmental origin of OA, and clarified the congenital and the living environment impact on the occurrence and development of OA. Our findings provide a theoretical and experimental basis for OA early prevention." smoking DOHAD
  • A new developmental mechanism for the separation of the mammalian middle ear ossicles from the jaw[4] "Multiple mammalian lineages independently evolved a definitive mammalian middle ear (DMME) through breakdown of Meckel's cartilage (MC). However, the cellular and molecular drivers of this evolutionary transition remain unknown for most mammal groups. Here, we identify such drivers in the living marsupial opossum Monodelphis domestica, whose MC transformation during development anatomically mirrors the evolutionary transformation observed in fossils. Specifically, we link increases in cellular apoptosis and TGF-BR2 signalling to MC breakdown in opossums. We demonstrate that a simple change in TGF-β signalling is sufficient to inhibit MC breakdown during opossum development, indicating that changes in TGF-β signalling might be key during mammalian evolution." Middle Ear Development
More recent papers  
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Search term: TGF-β Development | TGF-β Embryology

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Oocyte-derived BMP15 but not GDF9 down-regulates connexin43 expression and decreases gap junction intercellular communication (GJIC) activity in immortalized human granulosa cells[5] "In the ovary, connexin-coupled gap junctions in granulosa cells play crucial roles in follicular and oocyte development as well as in corpus luteum formation. ...The suppressive effects of BMP15 on Cx43 expression were further confirmed in primary human granulosa-lutein cells obtained from infertile patients undergoing an in vitro fertilization procedure. These findings suggest that oocyte-derived BMP15 decreases GJIC activity between human granulosa cells by down-regulating Cx43 expression, most likely via a Smad-dependent signaling pathway."
  • Spatio-temporal distribution of Smads and role of Smads/TGF-β/BMP-4 in the regulation of mouse bladder organogenesis[6] "Although Shh, TGF-β and BMP-4 regulate radial patterning of the bladder mesenchyme and smooth muscle differentiation, it is not known what transcription factors, local environmental cues or signaling cascades mediate bladder smooth muscle differentiation. ...Based on the Smad expression patterns, we suggest that individual or combinations of Smads may be necessary during mouse bladder organogenesis and may be critical mediators for bladder smooth muscle differentiation." Urinary Bladder Development


The TGF precursor protein has three distinct regions:

  1. signal peptide - targets it to the endoplasmic reticulum and secretion
  2. propeptide - or the latency associated peptide
  3. mature peptide - cleaved from the precursor protein and is actively involved in signalling
  • cleaved by Furin - a convertase
  • cleaved at a dibasic arginine-X-X-arginine (RXXR) site



Expressed at the fetal-maternal interface and implicated in the promotion of implantation and post-implantation development.[7]

Signaling Pathway

TGF-beta signaling pathway[8]


  1. active peptide forms a hetero- or homodimer
  2. binds to a specific TGF-β Type II receptor
  3. Type II receptor then recruits a TGF-β Type I receptor
  4. phosphorylates it via its serine/threonine kinase domain
  5. phosphorylated Type I receptors then phosphorylate receptor-associated Smad proteins (R-Smads), including Smad1/5 and Smad2/3
  • Type II receptor - MlTgfRII
  • Type I receptors - MlTgfRIa, MlTgfRIb, and MlTgfRIc

Intracellular Signaling

  • R-Smad proteins are composed of two main functional domains
    • Mad-homology domains 1 and 2 (MH1 and MH2)
  • Smad1/5 - associated with BMP-like signalling.
  • Smad2/3 - associated with TGF-β-like signaling.



Mothers against decapentaplegic homolog 5 (SMAD5) is a transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase.


Bone morphogenetic protein 15

BMP15 evolution among family members.jpg

BMP15 evolution among family members[9]

Growth Differentiation Factor 1

Growth Differentiation Factor 9 (GDF1) in involved in early left-right patterning.[10] Also expressed in the nervous systemin late-stage embryos.

Growth Differentiation Factor 9

Bovine ovarian follicle BMP15 and GDF9 expression[11]

Growth Differentiation Factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are both members of the transforming growth factor-β (TGF-β) superfamily. They have both been identified as growth factors required oocyte to granulosa cell signaling for ovarian follicle development (folliculogenesis).[12][13][14]

A recent study in pig has shown that oocyte-derived BMP15 but not GDF9 is required for down-regulation of connexin43 expression leading to a decrease in intercellular gap junction communication in granulosa cells.[5]

Links: TGF-beta | Bone Morphogenetic Protein | oocyte | ovary | menstrual cycle | OMIM - GDF9


A secretory protein (gene 10q22.1) important for gastrulation.[15] Nodal forms a heterodimer with Vg1 (GDF3) required for formation and mesendoderm induction.[16]


About OMIM "Online Mendelian Inheritance in Man OMIM is a comprehensive, authoritative, and timely compendium of human genes and genetic phenotypes. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and over 12,000 genes. OMIM focuses on the relationship between phenotype and genotype. It is updated daily, and the entries contain copious links to other genetics resources." OMIM


  1. Pang K, Ryan JF, Baxevanis AD & Martindale MQ. (2011). Evolution of the TGF-β signaling pathway and its potential role in the ctenophore, Mnemiopsis leidyi. PLoS ONE , 6, e24152. PMID: 21931657 DOI.
  2. Zinski J, Tajer B & Mullins MC. (2018). TGF-β Family Signaling in Early Vertebrate Development. Cold Spring Harb Perspect Biol , 10, . PMID: 28600394 DOI.
  3. Chen B, Lu KH, Ni QB, Li QX, Gao H, Wang H & Chen LB. (2019). Prenatal nicotine exposure increases osteoarthritis susceptibility in male elderly offspring rats via low-function programming of the TGFβ signaling pathway. Toxicol. Lett. , , . PMID: 31299270 DOI.
  4. Urban DJ, Anthwal N, Luo ZX, Maier JA, Sadier A, Tucker AS & Sears KE. (2017). A new developmental mechanism for the separation of the mammalian middle ear ossicles from the jaw. Proc. Biol. Sci. , 284, . PMID: 28179517 DOI.
  5. 5.0 5.1 Chang HM, Cheng JC, Taylor E & Leung PC. (2014). Oocyte-derived BMP15 but not GDF9 down-regulates connexin43 expression and decreases gap junction intercellular communication activity in immortalized human granulosa cells. Mol. Hum. Reprod. , 20, 373-83. PMID: 24413384 DOI.
  6. Islam SS, Mokhtari RB, Kumar S, Maalouf J, Arab S, Yeger H & Farhat WA. (2013). Spatio-temporal distribution of Smads and role of Smads/TGF-β/BMP-4 in the regulation of mouse bladder organogenesis. PLoS ONE , 8, e61340. PMID: 23620745 DOI.
  7. Jones RL, Stoikos C, Findlay JK & Salamonsen LA. (2006). TGF-beta superfamily expression and actions in the endometrium and placenta. Reproduction , 132, 217-32. PMID: 16885531 DOI.
  8. Pang K, Ryan JF, Baxevanis AD, Martindale MQ (2011) Evolution of the TGF-β Signaling Pathway and Its Potential Role in the Ctenophore, Mnemiopsis leidyi. PLoS ONE 6(9): e24152 PLoS ONE
  9. Auclair S, Rossetti R, Meslin C, Monestier O, Di Pasquale E, Pascal G, Persani L & Fabre S. (2013). Positive selection in bone morphogenetic protein 15 targets a natural mutation associated with primary ovarian insufficiency in human. PLoS ONE , 8, e78199. PMID: 24147118 DOI.
  10. Rankin CT, Bunton T, Lawler AM & Lee SJ. (2000). Regulation of left-right patterning in mice by growth/differentiation factor-1. Nat. Genet. , 24, 262-5. PMID: 10700179 DOI.
  11. Hosoe M, Kaneyama K, Ushizawa K, Hayashi KG & Takahashi T. (2011). Quantitative analysis of bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) gene expression in calf and adult bovine ovaries. Reprod. Biol. Endocrinol. , 9, 33. PMID: 21401961 DOI.
  12. McNatty KP, Moore LG, Hudson NL, Quirke LD, Lawrence SB, Reader K, Hanrahan JP, Smith P, Groome NP, Laitinen M, Ritvos O & Juengel JL. (2004). The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology. Reproduction , 128, 379-86. PMID: 15454632 DOI.
  13. Lodemann E & Wacker A. (1970). [Interferon-induction by Poly (A)-2 Poly (I)]. Naturwissenschaften , 57, 673. PMID: 5531364
  14. Lin ZL, Li YH, Xu YN, Wang QL, Namgoong S, Cui XS & Kim NH. (2014). Effects of growth differentiation factor 9 and bone morphogenetic protein 15 on the in vitro maturation of porcine oocytes. Reprod. Domest. Anim. , 49, 219-27. PMID: 24313324 DOI.
  15. Montague TG & Schier AF. (2017). Vg1-Nodal heterodimers are the endogenous inducers of mesendoderm. Elife , 6, . PMID: 29140251 DOI.
  16. Wei S & Wang Q. (2018). Molecular regulation of Nodal signaling during mesendoderm formation. Acta Biochim. Biophys. Sin. (Shanghai) , 50, 74-81. PMID: 29206913 DOI.


Cunha SI, Magnusson PU, Dejana E & Lampugnani MG. (2017). Deregulated TGF-β/BMP Signaling in Vascular Malformations. Circ. Res. , 121, 981-999. PMID: 28963191 DOI.


Huminiecki L, Goldovsky L, Freilich S, Moustakas A, Ouzounis C & Heldin CH. (2009). Emergence, development and diversification of the TGF-beta signalling pathway within the animal kingdom. BMC Evol. Biol. , 9, 28. PMID: 19192293 DOI.

Gadue P, Huber TL, Paddison PJ & Keller GM. (2006). Wnt and TGF-beta signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Proc. Natl. Acad. Sci. U.S.A. , 103, 16806-11. PMID: 17077151 DOI.

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