Developmental Signals - Bone Morphogenetic Protein

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Introduction

Belongs to the transforming growth factor-beta (TGFB) superfamily. The proteins are synthesized as prepropeptides, then cleaved, and then processed into dimeric proteins.


TGFB family members: TGFB1, TGFB, TGFB3, bone morphogenetic proteins Bmp-2A, Bmp-2B, Bmp-3, and Bmp-6. mullerian inhibitory substance.

Mouse Bmp4 expression face 01.jpg

Mouse Bmp4 expression face.[1]


BMP Mouse Links: Face and limb E9.5-13.5 | Face E9.5-13.5 | Body E11.0 | Body E11.5 | BMP | Mouse Development

Growth Differentiation Factor-6 (Gdf6) is a member of the Bone Morphogenetic Protein (BMP) family of secreted signaling molecules.

Factor Links: hCG | BMP | Sonic hedgehog | HOX | FGF | Nanog | Notch | FOX | PAX | Retinoic acid | SIX | Slit2/Robo1 | Sox | TBX | TGF-beta | VEGF | WNT | Hippo | Category:Molecular

Some Recent Findings

  • Bone morphogenetic protein 4 promotes craniofacial neural crest induction from human pluripotent stem cells[2] "Neural crest (NC) cells are a group of cells located in the neural folds at the boundary between the neural and epidermal ectoderm. Cranial NC cells migrate to the branchial arches and give rise to the majority of the craniofacial region, whereas trunk and tail NC cells contribute to the heart, enteric ganglia of the gut, melanocytes, sympathetic ganglia, and adrenal chromaffin cells. ...These BMP4-treated NC cells were capable of differentiation into osteocytes and chondrocytes. The results of the present study indicate that BMP4 regulates cranial positioning during NC development." Neural Crest Development
  • Review - EMBRYO DEVELOPMENT. BMP gradients: A paradigm for morphogen-mediated developmental patterning[3] "Bone morphogenetic proteins (BMPs) act in dose-dependent fashion to regulate cell fate choices in a myriad of developmental contexts. In early vertebrate and invertebrate embryos, BMPs and their antagonists establish epidermal versus central nervous system domains. In this highly conserved system, BMP antagonists mediate the neural-inductive activities proposed by Hans Spemann and Hilde Mangold nearly a century ago. BMPs distributed in gradients subsequently function as morphogens to subdivide the three germ layers into distinct territories and act to organize body axes, regulate growth, maintain stem cell niches, or signal inductively across germ layers. In this Review, we summarize the variety of mechanisms that contribute to generating reliable developmental responses to BMP gradients and other morphogen systems."
  • Construction of a vertebrate embryo from two opposing morphogen gradients[4] "Here, we show that opposing gradients of bone morphogenetic protein (BMP) and Nodal, two transforming growth factor family members that act as morphogens, are sufficient to induce molecular and cellular mechanisms required to organize, in vivo or in vitro, uncommitted cells of the zebrafish blastula animal pole into a well-developed embryo." Zebrafish Development
  • Developmental stalling and organ-autonomous regulation of morphogenesis[5] "Timing of organ development during embryogenesis is coordinated such that at birth, organ and fetal size and maturity are appropriately proportioned. The extent to which local developmental timers are integrated with each other and with the signaling interactions that regulate morphogenesis to achieve this end is not understood. Using the absolute requirement for a signaling pathway activity (bone morphogenetic protein, BMP) during a critical stage of tooth development, we show that suboptimal levels of BMP signaling do not lead to abnormal morphogenesis, as suggested by mutants affecting BMP signaling, but to a 24-h stalling of the intrinsic developmental clock of the tooth. During this time, BMP levels accumulate to reach critical levels whereupon tooth development restarts, accelerates to catch up with development of the rest of the embryo and completes normal morphogenesis. This suggests that individual organs can autonomously control their developmental timing to adjust their stage of development to that of other organs. We also find that although BMP signaling is critical for the bud-to-cap transition in all teeth, levels of BMP signaling are regulated differently in multicusped teeth. We identify an interaction between two homeodomain transcription factors, Barx1 and Msx1, which is responsible for setting critical levels of BMP activity in multicusped teeth and provides evidence that correlates the levels of Barx1 transcriptional activity with cuspal complexity. This study highlights the importance of absolute levels of signaling activity for development and illustrates remarkable self-regulation in organogenesis that ensures coordination of developmental processes such that timing is subordinate to developmental structure."
More recent papers
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
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References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Bone Morphogenetic Protein

Mehran Zarei-Ghanavati, Venkata Avadhanam, Alfonso Vasquez Perez, Christopher Liu The osteo-odonto-keratoprosthesis. Curr Opin Ophthalmol: 2017; PubMed 28441214

Marcelina Koćwin, Mateusz Jonakowski, Marcelina Przemęcka, Michał Panek, Piotr Kuna Selected bone morphogenetic proteins - the possibility of their use in the diagnostics and therapy of severe asthma. Adv Respir Med: 2017, 85(2);109-115 PubMed 28440536

Kaisaier Aji, Yun Zhang, Abudusaimi Aimaiti, Yujie Wang, Mulati Rexiati, Baihetiya Azhati, Hamulati Tusong, Lei Cui, Chen Wang MicroRNA-145 regulates the differentiation of human adipose-derived stem cells to smooth muscle cells via targeting Krüppel-like factor 4. Mol Med Rep: 2017; PubMed 28440409

Tsuyoshi Sato, Shoichiro Kokabu, Yuichiro Enoki, Naoki Hayashi, Masahito Matsumoto, Mitsuhiko Nakahira, Masashi Sugasawa, Tetsuya Yoda Functional Roles of Netrin-1 in Osteoblast Differentiation. In Vivo: 2017, 31(3);321-328 PubMed 28438858

Yohei Kanamori, Masaru Murakami, Makoto Sugiyama, Osamu Hashimoto, Tohru Matsui, Masayuki Funaba IL-1β transcriptionally activates hepcidin by inducing C/EBPδ expression in hepatocytes. J. Biol. Chem.: 2017; PubMed 28438835

Structure

BMP Superfamily Canonical Signalling
BMP superfamily canonical signalling.jpg
Over 30 bone morphogenetic protein (BMP) superfamily ligands have been discovered in humans. Most are secreted as mature disulfide-linked dimers, with the exception of TGF-β1, TGF-β2 and TGF-β3, which can be secreted in a latent form and require proteolytic activation. BMPs signal through a multimeric cell surface complex consisting of two type I receptors and two type II receptors.


Type I and type II BMP receptors are single pass transmembrane proteins with an intracellular serine/threonine kinase domain. After ligand binding, type II receptors phosphorylate (P) the type I receptors.

Activated type I receptors recruit and phosphorylate pathway-specific R-SMADs (SMAD1, SMAD5 and SMAD8 (blue pathway), and SMAD2 and SMAD3 (orange pathway)), which can form trimers with SMAD4 and translocate to the nucleus. SMADs have intrinsic DNA-binding activity and are able to regulate gene expression by recruitment of chromatin-remodelling machinery and integration with tissue-specific transcription factors. SMAD8 is also known as SMAD9.

The pathway can be antagonized by many mechanisms including neutralization of ligands by secreted traps such as noggin or follistatin, secretion of latent ligands bound to their propeptides, or via titration of receptors by nonsignalling ligands such as BMP3, activin β/inhibin α dimers or LEFTY monomers.

  • ACVR - activin receptor
  • ALK - activin receptor-like kinase
  • AMH - anti-Müllerian hormone
  • AMHR2 - AMH receptor 2
  • BMPR - BMP receptor
  • GDF - growth/differentiation factor
  • TGF - transforming growth factor
  • TGFBR - TGF-β receptor


Figure from recent BMP review.[6]

Gene

Function

Mouse Bmp4 expression limb and face 01.jpg

Mouse Bmp4 expression limb and face.[1]

Mouse face Bmp4 icon.jpg
 ‎‎Mouse Face Bmp4
Page | Play

Neural Development

During gastrulation the BMP pathway is antagonised and involved with neural induction. Neural induction signaling through the BMP-regulated Smad1/5 proteins appears to be controlled by fibroblast growth factor (FGF)-regulated Ca2+ entry activating calcineurin (CaN) that in turn dephosphorylates Smad1/5 proteins.[7]


Links: Neural Development

Oocyte Development

Ovarian follicle molecular interactions Bovine ovarian follicle BMP15 and GDF9
Molecular paracrine interactions involving BMP15 signaling[8] Localization of BMP15 in calf and cow follicles[9]
Links: Oocyte Development

Limb Development

Bmp2, Bmp4 and Bmp7 are co-required in the mouse AER for normal digit patterning but not limb outgrowth[10]

"Outgrowth and patterning of the vertebrate limb requires a functional apical ectodermal ridge (AER). The AER is a thickening of ectodermal tissue located at the distal end of the limb bud. Loss of this structure, either through genetic or physical manipulations results in truncation of the limb. A number of genes, including Bmps, are expressed in the AER. Previously, it was shown that removal of the BMP receptor Bmpr1a specifically from the AER resulted in complete loss of hindlimbs suggesting that Bmp signaling in the AER is required for limb outgrowth. In this report, we genetically removed the three known AER-expressed Bmp ligands, Bmp2, Bmp4 and Bmp7 from the AER of the limb bud using floxed conditional alleles and the Msx2-cre allele. Surprisingly, only defects in digit patterning and not limb outgrowth were observed. In triple mutants, the anterior and posterior AER was present but loss of the central region of the AER was observed. These data suggest that Bmp ligands expressed in the AER are not required for limb outgrowth but instead play an essential role in maintaining the AER and patterning vertebrate digits."

Limb AER BMP expression01.jpg


Links: Limb Development

Blood Vessel Development

BMP/SMAD signaling pathway regulates angiogenic sprouting and is involved in embryo vascular development.


Signaling Pathway

Identified BMP modulators:[11] Noggin, Chordin, Chordin-like 1, Chordin-like 2, Twisted gastrulation, Dan, BMPER, Sost, Sostdc1, Follistatin, Follistatin-like 1, Follistatin-like 5 and Tolloid.

Receptor

Intracellular Signaling

SNW-domain containing protein 1

(SNW1, SKI-INTERACTING PROTEIN; SKIIP)

A protein that interacts with nuclear receptors and enhances ligand-activated transcription, also called a nuclear receptor co-activator.


Regulator of Spatial BMP Activity, Neural Plate Border Formation, and Neural Crest Specification in Vertebrate Embryos[12]

"Bone morphogenetic protein (BMP) gradients provide positional information to direct cell fate specification, such as patterning of the vertebrate ectoderm into neural, neural crest, and epidermal tissues, with precise borders segregating these domains. However, little is known about how BMP activity is regulated spatially and temporally during vertebrate development to contribute to embryonic patterning, and more specifically to neural crest formation. Through a large-scale in vivo functional screen in Xenopus for neural crest fate, we identified an essential regulator of BMP activity, SNW1. SNW1 is a nuclear protein known to regulate gene expression. Using antisense morpholinos to deplete SNW1 protein in both Xenopus and zebrafish embryos, we demonstrate that dorsally expressed SNW1 is required for neural crest specification, and this is independent of mesoderm formation and gastrulation morphogenetic movements. By exploiting a combination of immunostaining for phosphorylated Smad1 in Xenopus embryos and a BMP-dependent reporter transgenic zebrafish line, we show that SNW1 regulates a specific domain of BMP activity in the dorsal ectoderm at the neural plate border at post-gastrula stages. We use double in situ hybridizations and immunofluorescence to show how this domain of BMP activity is spatially positioned relative to the neural crest domain and that of SNW1 expression. Further in vivo and in vitro assays using cell culture and tissue explants allow us to conclude that SNW1 acts upstream of the BMP receptors. Finally, we show that the requirement of SNW1 for neural crest specification is through its ability to regulate BMP activity, as we demonstrate that targeted overexpression of BMP to the neural plate border is sufficient to restore neural crest formation in Xenopus SNW1 morphants. We conclude that through its ability to regulate a specific domain of BMP activity in the vertebrate embryo, SNW1 is a critical regulator of neural plate border formation and thus neural crest specification."

Additional Images

OMIM

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


Links: OMIM300247

References

  1. 1.0 1.1 22701669</pubmed>| PLoS One
  2. Sumiyo Mimura, Mika Suga, Kaori Okada, Masaki Kinehara, Hiroki Nikawa, Miho K Furue Bone morphogenetic protein 4 promotes craniofacial neural crest induction from human pluripotent stem cells. Int. J. Dev. Biol.: 2016; PubMed 26934293
  3. Ethan Bier, Edward M De Robertis EMBRYO DEVELOPMENT. BMP gradients: A paradigm for morphogen-mediated developmental patterning. Science: 2015, 348(6242);aaa5838 PubMed 26113727
  4. Peng-Fei Xu, Nathalie Houssin, Karine F Ferri-Lagneau, Bernard Thisse, Christine Thisse Construction of a vertebrate embryo from two opposing morphogen gradients. Science: 2014, 344(6179);87-9 PubMed 24700857
  5. Isabelle Miletich, Wei-Yuan Yu, Ruofang Zhang, Kai Yang, Simone Caixeta de Andrade, Silvia Fontes do A Pereira, Atsushi Ohazama, Orin B Mock, Georg Buchner, Jane Sealby, Zoe Webster, Minglian Zhao, Marianna Bei, Paul T Sharpe Developmental stalling and organ-autonomous regulation of morphogenesis. Proc. Natl. Acad. Sci. U.S.A.: 2011, 108(48);19270-5 PubMed 22084104
  6. Valerie S Salazar, Laura W Gamer, Vicki Rosen BMP signalling in skeletal development, disease and repair. Nat Rev Endocrinol: 2016; PubMed 26893264
  7. Ahryon Cho, Yitai Tang, Jonathan Davila, Suhua Deng, Lei Chen, Erik Miller, Marius Wernig, Isabella A Graef Calcineurin signaling regulates neural induction through antagonizing the BMP pathway. Neuron: 2014, 82(1);109-24 PubMed 24698271
  8. Ewa Chronowska High-throughput analysis of ovarian granulosa cell transcriptome. Biomed Res Int: 2014, 2014;213570 PubMed 24711992 | PMC3966335 | Biomed Res Int.
  9. | PLoS One.
  10. Carlos I Lorda-Diez, Juan A Montero, Joaquin Rodriguez-Leon, Juan A Garcia-Porrero, Juan M Hurle Expression and functional study of extracellular BMP antagonists during the morphogenesis of the digits and their associated connective tissues. PLoS ONE: 2013, 8(4);e60423 PubMed 23573253
  11. Mary Y Wu, Marie-Christine Ramel, Michael Howell, Caroline S Hill SNW1 is a critical regulator of spatial BMP activity, neural plate border formation, and neural crest specification in vertebrate embryos. PLoS Biol.: 2011, 9(2);e1000593 PubMed 21358802

Reviews

Aena Pundir Jain, Siddharth Pundir, Anamika Sharma Bone morphogenetic proteins: The anomalous molecules. J Indian Soc Periodontol: 2013, 17(5);583-6 PubMed 24174749

Karen Ruschke, Christian Hiepen, Jessica Becker, Petra Knaus BMPs are mediators in tissue crosstalk of the regenerating musculoskeletal system. Cell Tissue Res.: 2012, 347(3);521-44 PubMed 22327483

Elisabetta Gazzerro, Ernesto Canalis Bone morphogenetic proteins and their antagonists. Rev Endocr Metab Disord: 2006, 7(1-2);51-65 PubMed 17029022

Di Chen, Ming Zhao, Gregory R Mundy Bone morphogenetic proteins. Growth Factors: 2004, 22(4);233-41 PubMed 15621726


Articles

Ahryon Cho, Yitai Tang, Jonathan Davila, Suhua Deng, Lei Chen, Erik Miller, Marius Wernig, Isabella A Graef Calcineurin signaling regulates neural induction through antagonizing the BMP pathway. Neuron: 2014, 82(1);109-24 PubMed 24698271

Yi-Jyun Luo, Yi-Hsien Su Opposing nodal and BMP signals regulate left-right asymmetry in the sea urchin larva. PLoS Biol.: 2012, 10(10);e1001402 PubMed 23055827

Elke Kuypers, Jennifer J P Collins, Reint K Jellema, Tim G A M Wolfs, Matthew W Kemp, Ilias Nitsos, J Jane Pillow, Graeme R Polglase, John P Newnham, Wilfred T V Germeraad, Suhas G Kallapur, Alan H Jobe, Boris W Kramer Ovine fetal thymus response to lipopolysaccharide-induced chorioamnionitis and antenatal corticosteroids. PLoS ONE: 2012, 7(5);e38257 PubMed 22693607


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Cite this page: Hill, M.A. 2017 Embryology Developmental Signals - Bone Morphogenetic Protein. Retrieved April 26, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Bone_Morphogenetic_Protein

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© Dr Mark Hill 2017, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G