Talk:Developmental Signals - Bone Morphogenetic Protein

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Cite this page: Hill, M.A. (2024, June 20) Embryology Developmental Signals - Bone Morphogenetic Protein. Retrieved from


Pharyngeal pouches provide a niche microenvironment for arch artery progenitor specification

Aihua Mao 1 , Mingming Zhang 1 , Linwei Li 1 , Jie Liu 1 , Guozhu Ning 1 , Yu Cao 1 , Qiang Wang 2 3 Affiliations expand PMID: 33334861 PMCID: PMC7847271 DOI: 10.1242/dev.192658 Free PMC article Abstract

The paired pharyngeal arch arteries (PAAs) are transient blood vessels connecting the heart with the dorsal aorta during embryogenesis. Although PAA malformations often occur along with pharyngeal pouch defects, the functional interaction between these adjacent tissues remains largely unclear. Here, we report that pharyngeal pouches are essential for PAA progenitor specification in zebrafish embryos. We reveal that the segmentation of pharyngeal pouches coincides spatiotemporally with the emergence of PAA progenitor clusters. These pouches physically associate with pharyngeal mesoderm in discrete regions and provide a niche microenvironment for PAA progenitor commitment by expressing BMP proteins. Specifically, pouch-derived BMP2a and BMP5 are the primary niche cues responsible for activating the BMP/Smad pathway in pharyngeal mesoderm, thereby promoting progenitor specification. In addition, BMP2a and BMP5 play an inductive function in the expression of the cloche gene npas4l in PAA progenitors. cloche mutants exhibit a striking failure to specify PAA progenitors and display ectopic expression of head muscle markers in the pharyngeal mesoderm. Therefore, our results support a crucial role for pharyngeal pouches in establishing a progenitor niche for PAA morphogenesis via BMP2a/5 expression.


Opening the Black Box - Stem Cell-Based Modeling of Human Post-Implantation Development

Taniguchi K, Heemskerk I & Gumucio DL. (2019). Opening the black box: Stem cell-based modeling of human post-implantation development. J. Cell Biol. , 218, 410-421. PMID: 30552099 DOI.

Proper development of the human embryo following its implantation into the uterine wall is critical for the successful continuation of pregnancy. However, the complex cellular and molecular changes that occur during this post-implantation period of human development are not amenable to study in vivo. Recently, several new embryo-like human pluripotent stem cell (hPSC)-based platforms have emerged, which are beginning to illuminate the current black box state of early human post-implantation biology. In this review, we will discuss how these experimental models are carving a way for understanding novel molecular and cellular mechanisms during early human development.

BMP controls dorsoventral and neural patterning in indirect-developing hemichordates providing insight into a possible origin of chordates

Proc Natl Acad Sci U S A. 2019 Jun 12. pii: 201901919. doi: 10.1073/pnas.1901919116. [Epub ahead of print]

Su YH1, Chen YC2, Ting HC2, Fan TP2, Lin CY2, Wang KT2, Yu JK1,3.

A defining feature of chordates is the unique presence of a dorsal hollow neural tube that forms by internalization of the ectodermal neural plate specified via inhibition of BMP signaling during gastrulation. While BMP controls dorsoventral (DV) patterning across diverse bilaterians, the BMP-active side is ventral in chordates and dorsal in many other bilaterians. How this phylum-specific DV inversion occurs and whether it is coupled to the emergence of the dorsal neural plate are unknown. Here we explore these questions by investigating an indirect-developing enteropneust from the hemichordate phylum, which together with echinoderms form a sister group of the chordates. We found that in the hemichordate larva, BMP signaling is required for DV patterning and is sufficient to repress neurogenesis. We also found that transient overactivation of BMP signaling during gastrulation concomitantly blocked mouth formation and centralized the nervous system to the ventral ectoderm in both hemichordate and sea urchin larvae. Moreover, this mouthless, neurogenic ventral ectoderm displayed a medial-to-lateral organization similar to that of the chordate neural plate. Thus, indirect-developing deuterostomes use BMP signaling in DV and neural patterning, and an elevated BMP level during gastrulation drives pronounced morphological changes reminiscent of a DV inversion. These findings provide a mechanistic basis to support the hypothesis that an inverse chordate body plan emerged from an indirect-developing ancestor by tinkering with BMP signaling. KEYWORDS: BMP; chordate origins; dorsoventral patterning; indirect-developing hemichordates; neural patterning PMID: 31189599 DOI: 10.1073/pnas.1901919116


BMP and FGF signaling interact to pattern mesoderm by controlling basic helix-loop-helix transcription factor activity

Elife. 2018 Jun 7;7. pii: e31018. doi: 10.7554/eLife.31018. [Epub ahead of print]

Row RH1, Pegg A2, Kinney B1, Farr GH3, Maves L3, Lowell S2, Wilson V4, Martin BL1.


The mesodermal germ layer is patterned into mediolateral subtypes by signaling factors including BMP and FGF. How these pathways are integrated to induce specific mediolateral cell fates is not well understood. We used mesoderm derived from post-gastrulation neuromesodermal progenitors (NMPs), which undergo a binary mediolateral patterning decision, as a simplified model to understand how FGF acts together with BMP to impart mediolateral fate. Using zebrafish and mouse NMPs, we identify an evolutionarily conserved mechanism of BMP and FGF mediated mediolateral mesodermal patterning that occurs through modulation of basic helix-loop-helix (bHLH) transcription factor activity. BMP imparts lateral fate through induction of Id helix loop helix (HLH) proteins, which antagonize bHLH transcription factors, induced by FGF signaling, that specify medial fate. We extend our analysis of zebrafish development to show that bHLH activity is responsible for the mediolateral patterning of the entire mesodermal germ layer. KEYWORDS: developmental biology; mouse; stem cells; zebrafish PMID: 29877796 DOI: 10.7554/eLife.31018


BMP signalling in skeletal development, disease and repair

Nat Rev Endocrinol. 2016 Apr;12(4):203-21. doi: 10.1038/nrendo.2016.12. Epub 2016 Feb 19.

Salazar VS1, Gamer LW1, Rosen V1.


Since the identification in 1988 of bone morphogenetic protein 2 (BMP2) as a potent inducer of bone and cartilage formation, BMP superfamily signalling has become one of the most heavily investigated topics in vertebrate skeletal biology. Whereas a large part of this research has focused on the roles of BMP2, BMP4 and BMP7 in the formation and repair of endochondral bone, a large number of BMP superfamily molecules have now been implicated in almost all aspects of bone, cartilage and joint biology. As modulating BMP signalling is currently a major therapeutic target, our rapidly expanding knowledge of how BMP superfamily signalling affects most tissue types of the skeletal system creates enormous potential to translate basic research findings into successful clinical therapies that improve bone mass or quality, ameliorate diseases of skeletal overgrowth, and repair damage to bone and joints. This Review examines the genetic evidence implicating BMP superfamily signalling in vertebrate bone and joint development, discusses a selection of human skeletal disorders associated with altered BMP signalling and summarizes the status of modulating the BMP pathway as a therapeutic target for skeletal trauma and disease.

PMID 26893264

Bone morphogenetic protein 4 promotes craniofacial neural crest induction from human pluripotent stem cells

Int J Dev Biol. 2016;60(1-2-3):21-28.

Mimura S1, Suga M, Okada K, Kinehara M, Nikawa H, Furue MK.


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. Positional information is indispensable for the regulation of cranial or trunk and tail NC cells. However, the mechanisms underlying the regulation of positional information during human NC induction have yet to be fully elucidated. In the present study, supplementation of bone morphogenetic protein (BMP) 4 in defined serum-free culture conditions including fibroblast growth factor-2 and Wnt3a from day 8 after NC specification induced the expression of cranial NC markers, AP2alpha, MSX1, and DLX1, during NC cell differentiation from human pluripotent stem cells. On the other hand, the proportion of cells expressing p75NTR or HNK1 decreased compared with that of cells cultured without BMP4, whereas gene expression analysis demonstrated that the expression levels of cranial NC-associated genes increased in BMP4-treated NC 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. PMID 26934293


Embryo Development. BMP gradients: A paradigm for morphogen-mediated developmental patterning

Science. 2015 Jun 26;348(6242):aaa5838. doi: 10.1126/science.aaa5838.

Bier E1, De Robertis EM2.


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. Copyright © 2015, American Association for the Advancement of Science.

PMID 26113727


Calcineurin signaling regulates neural induction through antagonizing the BMP pathway

Neuron. 2014 Apr 2;82(1):109-24. doi: 10.1016/j.neuron.2014.02.015.

Cho A1, Tang Y1, Davila J2, Deng S1, Chen L1, Miller E3, Wernig M2, Graef IA4.


Development of the nervous system begins with neural induction, which is controlled by complex signaling networks functioning in concert with one another. Fine-tuning of the bone morphogenetic protein (BMP) pathway is essential for neural induction in the developing embryo. However, the molecular mechanisms by which cells integrate the signaling pathways that contribute to neural induction have remained unclear. We find that neural induction is dependent on the Ca(2+)-activated phosphatase calcineurin (CaN). Fibroblast growth factor (FGF)-regulated Ca(2+) entry activates CaN, which directly and specifically dephosphorylates BMP-regulated Smad1/5 proteins. Genetic and biochemical analyses revealed that CaN adjusts the strength and transcriptional output of BMP signaling and that a reduction of CaN activity leads to an increase of Smad1/5-regulated transcription. As a result, FGF-activated CaN signaling opposes BMP signaling during gastrulation, thereby promoting neural induction and the development of anterior structures. Copyright © 2014 Elsevier Inc. All rights reserved.

PMID 24698271


Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression

Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):18940-5. doi: 10.1073/pnas.1310479110. Epub 2013 Oct 16.

Yoshimatsu Y, Lee YG, Akatsu Y, Taguchi L, Suzuki HI, Cunha SI, Maruyama K, Suzuki Y, Yamazaki T, Katsura A, Oh SP, Zimmers TA, Lee SJ, Pietras K, Koh GY, Miyazono K, Watabe T. Author information

Abstract Lymphatic vessels (LVs) play critical roles in the maintenance of fluid homeostasis and in pathological conditions, including cancer metastasis. Although mutations in ALK1, a member of the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) receptor family, have been linked to hereditary hemorrhagic telangiectasia, a human vascular disease, the roles of activin receptor-like kinase 1 (ALK-1) signals in LV formation largely remain to be elucidated. We show that ALK-1 signals inhibit LV formation, and LVs were enlarged in multiple organs in Alk1-depleted mice. These inhibitory effects of ALK-1 signaling were mediated by BMP-9, which decreased the number of cultured lymphatic endothelial cells. Bmp9-deficient mouse embryos consistently exhibited enlarged dermal LVs. BMP-9 also inhibited LV formation during inflammation and tumorigenesis. BMP-9 downregulated the expression of the transcription factor prospero-related homeobox 1, which is necessary to maintain lymphatic endothelial cell identity. Furthermore, silencing prospero-related homeobox 1 expression inhibited lymphatic endothelial cell proliferation. Our findings reveal a unique molecular basis for the physiological and pathological roles of BMP-9/ALK-1 signals in LV formation. KEYWORDS: angiogenesis, blood vascular endothelial cells, lymphangiogenesis

PMID 24133138

Bone morphogenetic proteins: The anomalous molecules

J Indian Soc Periodontol. 2013 Sep;17(5):583-586.

Jain AP, Pundir S, Sharma A. Author information

Abstract Bone is unique of all the tissues in the vertebrate organism. When injured, it heals by formation of new bone. Bone morphogenetic proteins (BMPs) are powerful inductors of the osteogenic activity during the embryologic bone formation phase and in cases of bone healing. They have proliferative effects on different cellular types, showing chemotactic properties and are able to induce mesenchymal cells differentiation into osteoblastic and chondroblastic line cells. Both primary cells and cell lines have been shown to respond to BMPs. Further the ability of embryonic cells to respond to BMPs by differentiating into cartilage and bone cells suggests that they are involved in the development of embryonic skeletal system. In addition, these proteins can also promote the angiogenesis, regulate the activity of some growth factors, and affect the production of these growth factors, which is helpful for the osteogenesis. BMPs have been considered as the most potent growth factors that can promote the bone regeneration. Thus, the aim of this review is to emphasize on the unique nature of the BMP molecules regarding their structure, classification, signaling mechanism, etc., as BMPs are the only molecules which show such deviation from the normal order, type. This will further help in understanding the role of BMPs and their potential advances which are necessary to facilitate the process of regeneration in periodontics. KEYWORDS: Bone, growth factors, healing, repair

PMID 24174749


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

PLoS One. 2012;7(5):e37826. doi: 10.1371/journal.pone.0037826. Epub 2012 May 25.

Choi KS1, Lee C, Maatouk DM, Harfe BD.


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. PMID 22662233

Opposing nodal and BMP signals regulate left-right asymmetry in the sea urchin larva

PLoS Biol. 2012;10(10):e1001402. doi: 10.1371/journal.pbio.1001402. Epub 2012 Oct 9.

Luo YJ, Su YH. Author information


Nodal and BMP signals are important for establishing left-right (LR) asymmetry in vertebrates. In sea urchins, Nodal signaling prevents the formation of the rudiment on the right side. However, the opposing pathway to Nodal signaling during LR axis establishment is not clear. Here, we revealed that BMP signaling is activated in the left coelomic pouch, specifically in the veg2 lineage, but not in the small micromeres. By perturbing BMP activities, we demonstrated that BMP signaling is required for activating the expression of the left-sided genes and the formation of the left-sided structures. On the other hand, Nodal signals on the right side inhibit BMP signaling and control LR asymmetric separation and apoptosis of the small micromeres. Our findings show that BMP signaling is the positive signal for left-sided development in sea urchins, suggesting that the opposing roles of Nodal and BMP signals in establishing LR asymmetry are conserved in deuterostomes.

PMID 23055827

Anti-Mullerian hormone (AMH) is induced by bone morphogenetic protein (BMP) cytokines in human granulosa cells

Eur J Obstet Gynecol Reprod Biol. 2012 Jun 7. [Epub ahead of print]

Ogura-Nose S, Yoshino O, Osuga Y, Shi J, Hiroi H, Yano T, Taketani Y. Source Department of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan. Abstract OBJECTIVES: Serum concentration of anti-Mullerian hormone (AMH) is used as a biomarker in clinical practice. Therefore, it is important to elucidate the mechanism by which AMH is regulated in granulosa cells (GC). An important first step in understanding AMH regulation is to determine which factors up-regulate AMH expression. STUDY DESIGN: Human GC, obtained from 28 women undergoing oocyte retrieval for in vitro fertilization, were stimulated with various intraovarian cytokines including bone morphogenetic protein (BMP)-2, -6, -7 -15, activin-A and growth differentiation factor (GDF)-9 (100ng/ml). The expression of AMH mRNA was evaluated with reverse transcription and quantitative real-time polymerase chain reaction (PCR), and AMH protein in cultured supernatant was measured with EIA kit. RESULTS: BMP-2, -6, -7 and -15, but not activin-A and GDF-9, significantly induced AMH expression in GC at mRNA and protein level, while all stimuli increased FSH receptor mRNA and decreased steroidogenic acute regulatory protein (StAR) mRNA level. CONCLUSIONS: Among the transforming growth factor (TGF)-β superfamily, BMP-2, -6, -7 and -15 significantly induced AMH expression in human GC. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

PMID 22682966


SNW1 Is a Critical Regulator of Spatial BMP Activity, Neural Plate Border Formation, and Neural Crest Specification in Vertebrate Embryos

PLoS Biol. 2011 Feb 15;9(2):e1000593. doi: 10.1371/journal.pbio.1000593.

Wu MY, Ramel MC, Howell M, Hill CS. Author information

Abstract 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. Comment in SNW1 orchestrates BMP signaling in early embryonic patterning. [PLoS Biol. 2011]

PMID 21358802

Developmental stalling and organ-autonomous regulation of morphogenesis

Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):19270-5. Epub 2011 Nov 14.

Miletich I, Yu WY, Zhang R, Yang K, Caixeta de Andrade S, Pereira SF, Ohazama A, Mock OB, Buchner G, Sealby J, Webster Z, Zhao M, Bei M, Sharpe PT. Source Department of Craniofacial Development, Dental Institute, Kings College London, Guys Hospital, London SE1 6RT, United Kingdom.


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.

PMID 22084104


BMP and BMP inhibitors in bone

Ann N Y Acad Sci. 2006 Apr;1068:19-25.

Rosen V. Author information

Abstract Bone morphogenetic proteins (BMPs) are signaling molecules that act locally on target cells to affect cell survival, proliferation, and differentiation. While first identified as bone-inducing agents, BMPs are now known to affect the formation and function of many organ systems. Here we focus only on the roles of BMPs in the skeleton. In the developing mouse embryo, BMPs direct skeletal patterning, chondrogenesis, and bone formation. In postnatal animals, BMPs are potent bone regeneration factors, affecting both the amount of new bone formed and the rate at which bone healing occurs. The amount of BMP available for signaling is tightly regulated in both the embryo and postnatally, and in the context of the skeleton, several structurally distinct BMP ligand antagonists have been shown to alter the ability of BMPs to bind to their receptors, blocking BMP activity in physiologically important circumstances. For example, noggin knockout mice display cartilage hyperplasia during skeletal development that results in the loss of joint formation (too much BMP activity), while mice that overexpress noggin in skeletal cells display severe osteopenia and bone fragility (too little BMP activity). Sclerostin, chordin, CTGF, follistatin, and gremlin are additional BMP antagonists that may act in the skeleton to regulate BMP availability. Another class of BMP inhibitors are the proteins that bind to BMP receptors but have no inherent signaling function and thus act as BMP receptor antagonists. To date, inhibin and BMP-3 have been identified as BMP receptor antagonists that can block BMP signaling in bone. Identification of BMP antagonists allows us to investigate their role in diseases that affect skeletal function, such as osteopenia and nonunion fracture, and may provide a novel therapeutic intervention point for treatment. PMID 16831902