View source for Bone morphogenetic protein 4

{{Short description|Human protein and coding gene}}
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{{Infobox gene}}
'''Bone morphogenetic protein 4''' is a [[protein]] that in humans is encoded by ''BMP4'' [[gene]].<ref name="van_den_Wijngaard_1995">{{cite journal | vauthors = van den Wijngaard A, Weghuis DO, Boersma CJ, van Zoelen EJ, Geurts van Kessel A, Olijve W | title = Fine mapping of the human bone morphogenetic protein-4 gene (BMP4) to chromosome 14q22-q23 by in situ hybridization | journal = Genomics | volume = 27 | issue = 3 | pages = 559–560 | date = November 1995 | pmid = 7558046 | doi = 10.1006/geno.1995.1096 | hdl = 2066/22049 | url = https://repository.ubn.ru.nl//bitstream/handle/2066/22050/22050___.PDF | hdl-access = free }}</ref><ref name="Oida_1995">{{cite journal | vauthors = Oida S, Iimura T, Maruoka Y, Takeda K, Sasaki S | title = Cloning and sequence of bone morphogenetic protein 4 (BMP-4) from a human placental cDNA library | journal = DNA Sequence : the Journal of DNA Sequencing and Mapping | volume = 5 | issue = 5 | pages = 273–275 | date = November 1995 | pmid = 7579580 | doi = 10.3109/10425179509030980 }}</ref> BMP4 is found on chromosome 14q22-q23.

BMP4 is a member of the [[bone morphogenetic protein]] family which is part of the [[transforming growth factor-beta]] superfamily. The [[Protein family|superfamily]] includes large families of growth and differentiation factors. BMP4 is highly conserved evolutionarily. BMP4 is found in early embryonic development in the ventral marginal zone and in the eye, heart blood and otic vesicle.<ref name="Knochel_2001">{{cite journal | vauthors = Knöchel S, Dillinger K, Köster M, Knöchel W | title = Structure and expression of Xenopus tropicalis BMP-2 and BMP-4 genes | journal = Mechanisms of Development | volume = 109 | issue = 1 | pages = 79–82 | date = November 2001 | pmid = 11677055 | doi = 10.1016/S0925-4773(01)00506-8 | s2cid = 792305 | doi-access = free }}</ref>

== Discovery ==
Bone morphogenetic proteins were originally identified by an ability of demineralized [[bone extract]] to induce [[endochondral]] osteogenesis in vivo in an extraskeletal site.

== Gene ==
Alternative splicing in the 5' untranslated region of this gene has been described and three variants are described, all encoding an identical protein.<ref>{{cite web | title = Entrez Gene: BMP4 bone morphogenetic protein 4 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=652 }}</ref>

== Structure ==
Yielding an active [[carboxy-terminal]] peptide of 116 residues, human bmp4 is initially synthesized as a forty percent residue preproprotein which is cleaved post translationally. BMP4 has seven residues which are conserved and glycosylated.<ref name="Aono_1995">{{cite journal | vauthors = Aono A, Hazama M, Notoya K, Taketomi S, Yamasaki H, Tsukuda R, Sasaki S, Fujisawa Y | title = Potent ectopic bone-inducing activity of bone morphogenetic protein-4/7 heterodimer | journal = Biochemical and Biophysical Research Communications | volume = 210 | issue = 3 | pages = 670–677 | date = May 1995 | pmid = 7763240 | doi = 10.1006/bbrc.1995.1712 }}</ref> The monomers are held with disulphide bridges and 3 pairs of cysteine amino acids. This conformation is called a "cystine knot". BMP4 can form homodimers or heterodimers with similar BMPS. One example of this is BMP7. This ability to form homodimers or heterodimers gives the ability to have greater [[Osteopromotive|osteoinductive]] activity than just bmp4 alone.<ref name="Botchkarev_1999">{{cite journal | vauthors = Botchkarev VA, Botchkareva NV, Roth W, Nakamura M, Chen LH, Herzog W, Lindner G, McMahon JA, Peters C, Lauster R, McMahon AP, Paus R | title = Noggin is a mesenchymally derived stimulator of hair-follicle induction | journal = Nature Cell Biology | volume = 1 | issue = 3 | pages = 158–164 | date = July 1999 | pmid = 10559902 | doi = 10.1038/11078 | s2cid = 8777441 }}</ref> Not much is known yet about how BMPS interact with the extracellular matrix. As well little is known about the pathways which then degrade BMP4.

== Function ==
BMP4 is a [[polypeptide]] belonging to the [[Transforming growth factor beta|TGF-β]] superfamily of proteins. Like other [[bone morphogenetic proteins]] (BMPs), it is critical for [[bone]] and [[cartilage]] development, including roles in [[tooth]] and [[limb]] formation and fracture repair. BMP4 is particularly important for initiating [[endochondral ossification]] in humans, and is also involved in muscle development, bone [[mineralization (biology)|mineralization]], and [[ureteric bud]] formation.<ref>{{cite journal | vauthors = Miyazaki Y, Oshima K, Fogo A, Hogan BL, Ichikawa I | title = Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter | journal = The Journal of Clinical Investigation | volume = 105 | issue = 7 | pages = 863–873 | date = April 2000 | pmid = 10749566 | pmc = 377476 | doi = 10.1172/JCI8256 }}</ref> It stimulates differentiation of ectodermal tissue,<ref>{{cite journal | vauthors = Biniazan F, Manzari-Tavakoli A, Safaeinejad F, Moghimi A, Rajaei F, Niknejad H | title = The differentiation effect of bone morphogenetic protein (BMP) on human amniotic epithelial stem cells to express ectodermal lineage markers | journal = Cell and Tissue Research | volume = 383 | issue = 2 | pages = 751–763 | date = February 2021 | pmid = 32960356 | doi = 10.1007/s00441-020-03280-z | s2cid = 221843254 }}</ref> and drives [[osteoblastic]] differentiation of [[mesenchymal stem cell]]s.{{citation needed|date=November 2012}}

=== Embryogenesis ===

==== Axis formation and mesoderm patterning ====
During embryogenesis, BMP4 is essential for dorsal–ventral axis specification and [[mesoderm]] patterning. In ''[[Xenopus]]'', BMP4 induces ventral mesoderm and suppresses neural fate by promoting epidermal differentiation.<ref name="HemmatiBrivanlou_1995">{{cite journal | vauthors = Hemmati-Brivanlou A, Thomsen GH | title = Ventral mesodermal patterning in Xenopus embryos: expression patterns and activities of BMP-2 and BMP-4 | journal = Developmental Genetics | volume = 17 | issue = 1 | pages = 78–89 | year = 1995 | pmid = 7554498 | doi = 10.1002/dvg.1020170109 }}</ref> In mice, loss of BMP4 results in impaired mesoderm formation.<ref>{{cite journal | vauthors = Winnier G, Blessing M, Labosky PA, Hogan BL | title = Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse | journal = Genes & Development | volume = 9 | issue = 17 | pages = 2105–2116 | date = September 1995 | pmid = 7657163 | doi = 10.1101/gad.9.17.2105 | doi-access = free }}</ref>

==== Neural Development ====
BMP4 plays a dorsalizing role in [[neural tube]] patterning, acting with [[BMP7]] from the roof plate to specify dorsal interneurons and counteract [[Sonic hedgehog]] (Shh) signaling from the floor plate.<ref name="Selleck_1998">{{cite journal | vauthors = Selleck MA, García-Castro MI, Artinger KB, Bronner-Fraser M | title = Effects of Shh and Noggin on neural crest formation demonstrate that BMP is required in the neural tube but not ectoderm | journal = Development | location = Cambridge, England | volume = 125 | issue = 24 | pages = 4919–4930 | date = December 1998 | pmid = 9811576 | doi = 10.1242/dev.125.24.4919 | url = https://authors.library.caltech.edu/16057/ | access-date = 22 August 2021 | archive-date = 20 May 2022 | archive-url = https://web.archive.org/web/20220520235003/https://authors.library.caltech.edu/16057/ | url-status = dead }}</ref>
It also contributes to neural crest cell apoptosis in the hindbrain region.<ref>{{cite journal | vauthors = Graham A, Francis-West P, Brickell P, Lumsden A | title = The signalling molecule BMP4 mediates apoptosis in the rhombencephalic neural crest | journal = Nature | volume = 372 | issue = 6507 | pages = 684–686 | date = December 1994 | pmid = 7990961 | doi = 10.1038/372684a0 | bibcode = 1994Natur.372..684G | s2cid = 4361935 }}</ref>

==== Somites and cartilage ====
BMP4 is involved in somite patterning and promotes cartilage development by inducing the expression of [[Homeobox protein MSX-1|Msx1]] and [[Homeobox protein MSX-2|Msx2]] genes in the somatic mesoderm.<ref>{{cite book | vauthors = Wolpert L, Tickle C, Arias AM, Lawrence P, Lumsden A, Robertson E, Meyerowitz E, Smith J | chapter = Vertebrate development III: Chick and mouse - completing the body plan | title = Principles of development | location = Oxford, United Kingdom | publisher = Oxford University Press | pages = 207 | date = 2015 | isbn = 978-0-19-870988-6 | edition = Fifth }}</ref><ref name="Watanabe_1996">{{cite journal | vauthors = Watanabe Y, Le Douarin NM | title = A role for BMP-4 in the development of subcutaneous cartilage | journal = Mechanisms of Development | volume = 57 | issue = 1 | pages = 69–78 | date = June 1996 | pmid = 8817454 | doi = 10.1016/0925-4773(96)00534-5 | s2cid = 16858412 | doi-access = free }}</ref>

==== Organogenesis ====
BMP4 plays key roles in the development of multiple organs.  In Limb buds, BMP4 is expressed in interdigital mesenchyme, where it prevents apoptosis and contributes to digit separation.<ref name="ArteagaSolis_2001">{{cite journal | vauthors = Arteaga-Solis E, Gayraud B, Lee SY, Shum L, Sakai L, Ramirez F | title = Regulation of limb patterning by extracellular microfibrils | journal = The Journal of Cell Biology | volume = 154 | issue = 2 | pages = 275–281 | date = July 2001 | pmid = 11470817 | pmc = 2150751 | doi = 10.1083/jcb.200105046 }}</ref>  In teeth, it induces transcription factors Msx1 and Msx2 to specify incisor identity.
Kidneys and urinary tract: BMP4 promotes ureteric bud branching and ureter differentiation.<ref name="Miyazaki_2003">{{cite journal | vauthors = Miyazaki Y, Oshima K, [[Agnes Fogo | Fogo A]], Ichikawa I | title = Evidence that bone morphogenetic protein 4 has multiple biological functions during kidney and urinary tract development | journal = Kidney International | volume = 63 | issue = 3 | pages = 835–844 | date = March 2003 | pmid = 12631064 | doi = 10.1046/j.1523-1755.2003.00834.x | doi-access = free }}</ref>  In lung and liver: BMP4 expression contributes to early organ specification and branching morphogenesis.

==== Stem cell differentiation ====
BMP4 synergizes with [[FGF2]] to promote [[pluripotent stem cell]] differentiation into mesodermal lineages, enhancing [[osteogenic]] and [[chondrogenic]] outcomes.<ref name="Lee_2013">{{cite journal | vauthors = Lee TJ, Jang J, Kang S, Jin M, Shin H, Kim DW, Kim BS | title = Enhancement of osteogenic and chondrogenic differentiation of human embryonic stem cells by mesodermal lineage induction with BMP-4 and FGF2 treatment | journal = Biochemical and Biophysical Research Communications | volume = 430 | issue = 2 | pages = 793–797 | date = January 2013 | pmid = 23206696 | doi = 10.1016/j.bbrc.2012.11.067 }}</ref> Together, BMP4 and FGF2 can also direct differentiation toward [[thyroid]] progenitor cells.<ref name="Kurmann_2015">{{cite journal | vauthors = Kurmann AA, Serra M, Hawkins F, Rankin SA, Mori M, Astapova I, Ullas S, Lin S, Bilodeau M, Rossant J, Jean JC, Ikonomou L, Deterding RR, Shannon JM, Zorn AM, Hollenberg AN, Kotton DN | title = Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells | journal = Cell Stem Cell | volume = 17 | issue = 5 | pages = 527–542 | date = November 2015 | pmid = 26593959 | pmc = 4666682 | doi = 10.1016/j.stem.2015.09.004 | language = en }}</ref>

=== Adult ===

==== Nervous System ====
In the adult brain, BMP4 regulates ongoing [[neurogenesis]] in the [[dentate gyrus]] and [[subventricular zone]] (SVZ):
In the dentate gyrus, BMP4 maintains neural stem cells in a quiescent state via BMPR-IA signaling.<ref>{{Cite journal | vauthors = Mira H, Andreu Z, Suh H, Lie DC, Jessberger S, Consiglio A, San Emeterio J, Hortigüela R, Marqués-Torrejón MA, Nakashima K, Colak D, Götz M, Fariñas I, Gage FH | title = Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus | journal = Cell Stem Cell | volume = 7 | issue = 1 | pages = 78–89 | date = Jul 2010 | pmid = 20621052 | doi = 10.1016/j.stem.2010.04.016 | doi-access = free }}</ref>

In the SVZ, BMP4 promotes neuronal over oligodendroglial lineage commitment via Smad4 signaling<ref>{{Cite journal | vauthors = Colak D, Mori T, Brill MS, Pfeifer A, Falk S, Deng C, Monteiro R, Mummery C, Sommer L, Götz M | title = Adult neurogenesis requires Smad4-mediated bone morphogenic protein signaling in stem cells | journal = The Journal of Neuroscience : the Official Journal of the Society for Neuroscience | volume = 28 | issue = 2 | pages = 434–446 | date = Jan 2008 | pmid = 18184786 | pmc = 6670509 | doi = 10.1523/JNEUROSCI.4374-07.2008 }}</ref> and works with [[Tis21]]/[[BTG2]] to promote terminal neuronal differentiation.<ref name="FarioliVecchioli_2014">{{cite journal | vauthors = Farioli-Vecchioli S, Ceccarelli M, Saraulli D, Micheli L, Cannas S, D'Alessandro F, Scardigli R, Leonardi L, Cinà I, Costanzi M, Mattera A, Cestari V, Tirone F | title = Tis21 is required for adult neurogenesis in the subventricular zone and for olfactory behavior regulating cyclins, BMP4, Hes1/5 and Ids | journal = Frontiers in Cellular Neuroscience | volume = 8 | pages = 98 | year = 2014 | pmid = 24744701 | pmc = 3977348 | doi = 10.3389/fncel.2014.00098 | doi-access = free }}</ref>

==== Metabolism and adipose tissue ====
BMP4 plays metabolic roles by regulating [[adipogenesis]]. It promotes differentiation of white adipocytes. It induces [[UCP1]] expression in brown adipose tissue, supporting [[non-shivering thermogenesis]].<ref name="BlazquezMedela_2019">{{cite journal | vauthors = Blázquez-Medela AM, Jumabay M, Boström KI | title = Beyond the bone: Bone morphogenetic protein signaling in adipose tissue | journal = Obesity Reviews : an Official Journal of the International Association for the Study of Obesity | volume = 20 | issue = 5 | pages = 648–658 | date = May 2019 | pmid = 30609449 | pmc = 6447448 | doi = 10.1111/obr.12822 }}</ref>

==== Reproductive system ====
In the ovary, BMP4 (in conjunction with BMP7) supports early folliculogenesis and promotes the survival of primordial follicles.<ref name="Nilsson_2003">{{cite journal | vauthors = Nilsson EE, Skinner MK | title = Bone morphogenetic protein-4 acts as an ovarian follicle survival factor and promotes primordial follicle development | journal = Biology of Reproduction | volume = 69 | issue = 4 | pages = 1265–1272 | date = October 2003 | pmid = 12801979 | doi = 10.1095/biolreprod.103.018671 | s2cid = 2141586 }}</ref>

=== Birds ===
In [[Darwin's finches]], variation in BMP4 expression during beak development contributes to differences in beak size and shape, demonstrating its evolutionary role in morphological diversity.<ref name="Abzhanov_2004">{{cite journal | vauthors = Abzhanov A, Protas M, Grant BR, Grant PR, Tabin CJ | title = Bmp4 and morphological variation of beaks in Darwin's finches | journal = Science | location = New York, N.Y. | volume = 305 | issue = 5689 | pages = 1462–1465 | date = September 2004 | pmid = 15353802 | doi = 10.1126/science.1098095 | bibcode = 2004Sci...305.1462A | s2cid = 17226774 }}</ref>

=== Signal transduction ===
BMP4, as a member of the transforming growth factor-β (TGF-β) family binds to 2 different types of serine-threonine kinase receptors known as BMPR1 and BMPR2.<ref name="Miyazono_2010" /> Signal transduction via these receptors occurs via Smad and map [[kinase]] pathways to effect [[transcription (genetics)|transcription]] of its target genes. In order for signal transduction to occur, both receptors must be functional. BMP is able to bind to BMPR2 without BMPR1 however, the affinity significantly increases in the presence of both receptors. BMPR1 is transphosphorylated via BMPR2 which induces downstream signalling within the cell, affecting transcription.<ref name="Miyazono_2010">{{cite journal | vauthors = Miyazono K, Kamiya Y, Morikawa M | title = Bone morphogenetic protein receptors and signal transduction | journal = Journal of Biochemistry | volume = 147 | issue = 1 | pages = 35–51 | date = January 2010 | pmid = 19762341 | doi = 10.1093/jb/mvp148 | doi-access = free }}</ref>

==== Smad signaling pathway ====
TGF-β family receptors most commonly use the [[SMAD (protein)|Smad]] signaling pathway to tranduce signals.<ref name="Miyazono_2010" /> Type 2 receptors are responsible for activating type 1 [[receptor (biochemistry)|receptor]]s where their function involves the phosphorylation of R-Smads (Smad-1, Smad-5, Smad-8). Upon phosphorylation, formation of an [[R-SMAD]] complex in conjunction with common-partner Smad (co-Smad) occurs where it migrates to the nucleus. This signaling [[Signaling pathway|pathway]] is regulated by the small molecule inhibitor known as dorsomorphin which prevents the downstream effects of R-smads.<ref name="Miyazono_2010" />

==== Map kinase (MAPK) signaling pathways ====
[[Mitogen]] activated protein kinases (MAPK) undergo phosphorylation via a signaling cascade where MAPKKK phosphorylates and activates MAPKK and MAPKK phosphorylates and activates [[MAPK]] which then induces an intracellular response.<ref name="Cell_2012">{{cite web | work = Cell Signaling Technology, Inc. | title = Mitogen-Activated Protein Kinase Cascades | url = http://www.cellsignal.com/reference/pathway/MAPK_Cascades.html | access-date = 17 November 2012 }}</ref> Activation of MAPKKK is through the interaction of mainly GTPases or another group of protein kinases. TGF-β receptors induce the MAPK signaling pathways of ERK, JNK and p38.<ref name="Cell_2012" /> BMP4 is also known to activate the ERK, JNK and p38 MAPK signalling pathways whilst have been found to act independently of Smad signaling pathways, are mostly active in conjunction with Smad.<ref name="Derynck_2003">{{cite journal | vauthors = Derynck R, Zhang YE | title = Smad-dependent and Smad-independent pathways in TGF-beta family signaling | journal = Nature | volume = 425 | issue = 6958 | pages = 577–584 | date = October 2003 | pmid = 14534577 | doi = 10.1038/nature02006 | bibcode = 2003Natur.425..577D | s2cid = 4419607 }}</ref> The activation of the ERK and JNK pathways acts to phosphorylate Smad and therefore regulate its activation. In addition to this, MAPK pathways may be able to directly affect Smad-interacting transcription factors via a JNK or p38 substrate that induces convergence of the two signaling pathways. This convergence is noted to consist mainly of cooperative behavior however, there is evidence to suggest that they may at times counteract each other. Furthermore, the balance that exists between the direct activation of these signaling pathways has a significant effect on TGF-β induced cellular responses.<ref name="Derynck_2003" />

[[File:Generation-of-Trophoblast-Stem-Cells-from-Rabbit-Embryonic-Stem-Cells-with-BMP4-pone.0017124.s005.ogv|thumb|Generation-of-Trophoblast-Stem-Cells-from-Rabbit-Embryonic-Stem-Cells-with-BMP4-pone.0017124.s005]]

== Inhibition ==
Inhibition of the BMP4 signal (by [[chordin]], [[noggin (protein)|noggin]], or [[follistatin]]) causes the ectoderm to differentiate into the [[neural plate]]. If these cells also receive signals from [[Fibroblast growth factor|FGF]], they will differentiate into the spinal cord; in the absence of FGF the cells become brain tissue.

While overexpression of BMP4 expression can lead to ventralization, inhibition with a dominant negative may result in complete dorsalization of the embryo or the formation of two axises.<ref name="Metz_1998">{{cite journal | vauthors = Metz A, Knöchel S, Büchler P, Köster M, Knöchel W | title = Structural and functional analysis of the BMP-4 promoter in early embryos of Xenopus laevis | journal = Mechanisms of Development | volume = 74 | issue = 1–2 | pages = 29–39 | date = June 1998 | pmid = 9651472 | doi = 10.1016/S0925-4773(98)00059-8 | s2cid = 14496024 | doi-access = free }}</ref>

It is important to note that mice in which BMP4 was completely inactivated usually died during [[gastrulation]]. It is thought that inactivation of human BMP4 would likely have the same effect. However, mutations which don't entirely inactivate BMP4 in humans can also have subtle effects phenotypically, and have been implicated in [[tooth agenesis]] as well as osteoporosis.<ref>{{cite journal | vauthors = Yu M, Wang H, Fan Z, Xie C, Liu H, Liu Y, Han D, Wong SW, Feng H | title = BMP4 mutations in tooth agenesis and low bone mass | journal = Archives of Oral Biology | volume = 103 | pages = 40–46 | date = July 2019 | pmid = 31128441 | pmc = 6639811 | doi = 10.1016/j.archoralbio.2019.05.012 }}</ref>

== Clinical significance ==
Increase in expression of BMP4 has been associated with a variety of bone diseases, including the heritable disorder [[Fibrodysplasia Ossificans Progressiva]].<ref name="Kan_2004">{{cite journal | vauthors = Kan L, Hu M, Gomes WA, Kessler JA | title = Transgenic Mice Overexpressing BMP4 Develop a Fibrodysplasia Ossificans Progressiva (FOP)-Like Phenotype | journal = The American Journal of Pathology | volume = 165 | issue = 4 | pages = 1107–1115 | date = October 2004 | pmid = 15466378 | pmc = 1618644 | doi = 10.1016/S0002-9440(10)63372-X }}</ref>

There is strong evidence from sequencing studies of candidate genes involved in clefting that mutations in the bone morphogenetic protein 4 (BMP4) gene may be associated in the pathogenesis of [[cleft lip and palate]].<ref name="Dixon_2011">{{cite journal | vauthors = Dixon MJ, Marazita ML, Beaty TH, Murray JC | title = Cleft lip and palate: understanding genetic and environmental influences | journal = Nature Reviews. Genetics | volume = 12 | issue = 3 | pages = 167–178 | date = March 2011 | pmid = 21331089 | pmc = 3086810 | doi = 10.1038/nrg2933 }}</ref>

=== Eye development ===
Eyes are essential for organisms, especially [[terrestrial animal|terrestrial]] vertebrates, to observe prey and obstacles; this is critical for their survival. The formation of the eyes starts as optic vesicles and lens derived from the [[neuroectoderm]]. Bone morphogenic proteins are known to stimulate eye lens formation.
During early development of eyes, the formation of the [[optic vesicle]] is essential in Mice and BMP4 expressed strongly in the optic vesicle and weakly in the surrounding [[mesenchyme]] and surface ectoderm. This concentration gradient of BMP4 in optic vesicle is critical for lens induction. Researcher, Dr. Furuta and Dr. Hogan found out that if they did a laser mutation on mice embryos and causing a BMP4 [[homozygous]] null [[mutation]], this embryo will not develop the lens. They also did an in situ [[Nucleic acid hybridisation|hybridization]] of the BMP4 [[gene]] showing green color and [[Sox2]] gene in red which they thought it was involved in the lens formation as well. After they did these two in situ hybridizations in the mice embryos, they found that both green and red colors are found in the optic [[Optic vesicles|vesicle]] of the mice embryos. This indicated that BMP4 and [[Sox2]] are expressed in the right place at the right time of the optic vesicle and prove that they have some essential functions for the lens induction. Furthermore, they did a follow-up experiment that by injecting BMP4 into the BMP4 [[homozygous]] mutant embryos rescued the lens formation (12). This indicated that BMP4 is definitely required for lens formation. However, researchers also found that some of the mutated mice cannot be rescued. They later found that those mutants lacked of [[Msh homeobox 2|Msx 2]] which is activated by BMP4. The mechanism they predicted was that BMP4 will active Msx 2 in the optic vesicle and concentration combination of BMP4 and Msx2 together active Sox2 and the Sox2 is essential for lens differentiation.<ref name="Furuta_1998">{{cite journal | vauthors = Furuta Y, Hogan BL | title = BMP4 is essential for lens induction in the mouse embryo | journal = Genes & Development | volume = 12 | issue = 23 | pages = 3764–3775 | date = December 1998 | pmid = 9851982 | pmc = 317259 | doi = 10.1101/gad.12.23.3764 }}</ref>

Injection of Noggin into lens fiber cells in mice significantly reduces the BMP4 proteins in the cells. This indicates that Noggin is sufficient to inhibit the production of BMP4. Moreover, another [[inhibitor protein]], Alk6 was found that blocked the BMP4 from activating the Msx2 which stopped lens differentiation .<ref name="Faber_2002">{{cite journal | vauthors = Faber SC, Robinson ML, Makarenkova HP, Lang RA | title = Bmp signaling is required for development of primary lens fiber cells | journal = Development | location = Cambridge, England | volume = 129 | issue = 15 | pages = 3727–3737 | date = August 2002 | pmid = 12117821 | doi = 10.1242/dev.129.15.3727 }}</ref> However, there are still a lot of unknown about the mechanism of inhibition on BMP4 and downstream regulation of Sox2. In the future, researchers are aiming to find out a more complete pathway of whole eye development and hoping one day, they can find a way to cure some genetic caused eye diseases.

=== Hair loss ===
Hair loss or known as [[alopecia]] is caused from the changing of [[hair follicle]] morphology and hair follicle cycling in an abnormal fashion.<ref name="Cotsarelis_2001">{{cite journal | vauthors = Cotsarelis G, Millar SE | title = Towards a molecular understanding of hair loss and its treatment | journal = Trends in Molecular Medicine | volume = 7 | issue = 7 | pages = 293–301 | date = July 2001 | pmid = 11425637 | doi = 10.1016/S1471-4914(01)02027-5 }}</ref> The cycles of hair follicles are that of growth, or [[anagen]], regression or [[catagen]], and rest or [[telogen]].<ref name="Millar_2002">{{cite journal | vauthors = Millar SE | title = Molecular mechanisms regulating hair follicle development | journal = The Journal of Investigative Dermatology | volume = 118 | issue = 2 | pages = 216–225 | date = February 2002 | pmid = 11841536 | doi = 10.1046/j.0022-202x.2001.01670.x | doi-access = free }}</ref> In mammals reciprocal epithelial and mesenchymal interactions control the development of hair. Genes such as BMP4 and [[Bone morphogenetic protein 2|BMP2]] are both active within the precursors of the hair shaft. Specifically BMP4 is found in the [[dermal papilla]]. BMP4 is part of the signaling network which controls the development of hair. It is needed for the induction of biochemical pathways and signaling for regulating the differentiation of the hair shaft in the anagen hair follicle. This is done through controlling the expression of the [[transcription factors]] which regulate hair differentiation. It is still unclear however where BMPs act within the genetic network. The signaling of bmp4 may potentially control expression of terminal differentiation molecules such as keratins. Other regulators have been shown to control hair follicle development as well. [[HOXC13]] and [[FOXN1]] are considered important regulators because loss-of-function experiments show impaired hair shaft differentiation that doesn't interfere in the hair follicle formation.<ref name="Kulessa_2000">{{cite journal | vauthors = Kulessa H, Turk G, Hogan BL | title = Inhibition of Bmp signaling affects growth and differentiation in the anagen hair follicle | journal = The EMBO Journal | volume = 19 | issue = 24 | pages = 6664–6674 | date = December 2000 | pmid = 11118201 | pmc = 305899 | doi = 10.1093/emboj/19.24.6664 }}</ref>

When BMP4 is expressed ectopically, within transgenic mice the hair follicle [[outer root sheath]] (ORS) the proliferation of the cell matrix is inhibited. BMP4 also activates hair [[keratin]] gene expression noting that BMP4 is important in the differentiation of the hair shaft. [[Noggin (protein)|Noggin]], a known inhibitor of BMP4, is found within the matrix cells of the hair bulb. Other important factors to consider in the development of hair is the expression of Shh ([[sonic hedgehog]]), [[BMP7]], BMP2, [[Wnt signaling pathway|WNT]], and [[beta-catenin|β-catenin]] as these are required in early stage [[morphogenesis]].<ref name="Huelsken_2001">{{cite journal | vauthors = Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W | title = beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin | journal = Cell | volume = 105 | issue = 4 | pages = 533–545 | date = May 2001 | pmid = 11371349 | doi = 10.1016/S0092-8674(01)00336-1 | s2cid = 16775006 | doi-access = free }}</ref>

Other genes which can inhibit or interact with BMP4 are noggin, [[follistatin]], [[gremlin]], which is all expressed in the developing hair follicles.<ref name="Feijen_1994">{{cite journal | vauthors = Feijen A, Goumans MJ, van den Eijnden-van Raaij AJ | title = Expression of activin subunits, activin receptors and follistatin in postimplantation mouse embryos suggests specific developmental functions for different activins | journal = Development | location = Cambridge, England | volume = 120 | issue = 12 | pages = 3621–3637 | date = December 1994 | pmid = 7821227 | doi = 10.1242/dev.120.12.3621 }}</ref> In mice in which noggin is lacking, there are fewer hair follicles than on a normal mouse and the development of the [[Hair follicle|follicle]] is inhibited. In chick embryos it is shown that ectopically expressed noggin produces enlarged follicles, and BMP4 signaling shows repressed placode fate in nearby cells.<ref name="Botchkarev_1999" /> Noggin has also been shown during in vivo experiments to induce hair growth in post natal skin.<ref name="Botchkarev_2001">{{cite journal | vauthors = Botchkarev VA, Botchkareva NV, Nakamura M, Huber O, Funa K, Lauster R, Paus R, Gilchrest BA | title = Noggin is required for induction of the hair follicle growth phase in postnatal skin | journal = FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology | volume = 15 | issue = 12 | pages = 2205–2214 | date = October 2001 | pmid = 11641247 | doi = 10.1096/fj.01-0207com | s2cid = 10236217 | doi-access = free }}</ref>

BMP4 is an important component of the biological pathways that involved regulating hair shaft differentiation within the anagen hair follicle. The strongest levels of expressed BMP4 are found within the [[medulla (hair)|medulla]], hair shaft cells, distal hair matrix, and potential precursors of the [[cuticle]]. The two main methods which BMP4 inhibit expression of hair is through restricting growth factor expression in the hair matrix and antagonism between growth and differentiation signaling.<ref name="Huelsken_2001" />

Pathways that regulate hair follicle formation and hair growth are key in developing therapeutic methods for hair loss conditions. Such conditions include the development of new follicles, changing the shape of characteristics of existing follicles, and the altering of hair growth in existing hair follicles. Furthermore, BMP4 and the pathway through which it works may provide therapeutic targets for the prevention of hair loss.<ref name="Millar_2002" />

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA | title = Novel regulators of bone formation: molecular clones and activities | journal = Science | location = New York, N.Y. | volume = 242 | issue = 4885 | pages = 1528–1534 | date = Dec 1988 | pmid = 3201241 | doi = 10.1126/science.3201241 | bibcode = 1988Sci...242.1528W }}
* {{cite journal | vauthors = Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, ten Dijke P, Heldin CH, Miyazono K | title = Cloning and characterization of a human type II receptor for bone morphogenetic proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 17 | pages = 7632–7636 | date = Aug 1995 | pmid = 7644468 | pmc = 41199 | doi = 10.1073/pnas.92.17.7632 | bibcode = 1995PNAS...92.7632R | doi-access = free }}
* {{cite journal | vauthors = Nohno T, Ishikawa T, Saito T, Hosokawa K, Noji S, Wolsing DH, Rosenbaum JS | title = Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors | journal = Journal of Biological Chemistry | volume = 270 | issue = 38 | pages = 22522–22526 | date = Sep 1995 | pmid = 7673243 | doi = 10.1074/jbc.270.38.22522 | doi-access = free }}
* {{cite journal | vauthors = Yamaji N, Celeste AJ, Thies RS, Song JJ, Bernier SM, Goltzman D, Lyons KM, Nove J, Rosen V, Wozney JM | title = A mammalian serine/threonine kinase receptor specifically binds BMP-2 and BMP-4 | journal = Biochemical and Biophysical Research Communications | volume = 205 | issue = 3 | pages = 1944–1951 | date = Dec 1994 | pmid = 7811286 | doi = 10.1006/bbrc.1994.2898 }}
* {{cite journal | vauthors = Harris SE, Harris MA, Mahy P, Wozney J, Feng JQ, Mundy GR | title = Expression of bone morphogenetic protein messenger RNAs by normal rat and human prostate and prostate cancer cells | journal = The Prostate | volume = 24 | issue = 4 | pages = 204–211 | date = Apr 1994 | pmid = 8146069 | doi = 10.1002/pros.2990240406 | s2cid = 21276656 }}
* {{cite journal | vauthors = van den Wijngaard A, van Kraay M, van Zoelen EJ, Olijve W, Boersma CJ | title = Genomic organization of the human bone morphogenetic protein-4 gene: molecular basis for multiple transcripts | journal = Biochemical and Biophysical Research Communications | volume = 219 | issue = 3 | pages = 789–794 | date = Feb 1996 | pmid = 8645259 | doi = 10.1006/bbrc.1996.0312 | hdl = 2066/23948 | url = https://repository.ubn.ru.nl//bitstream/handle/2066/28474/28474.pdf | hdl-access = free }}
* {{cite journal | vauthors = Nishitoh H, Ichijo H, Kimura M, Matsumoto T, Makishima F, Yamaguchi A, Yamashita H, Enomoto S, Miyazono K | title = Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5 | journal = Journal of Biological Chemistry | volume = 271 | issue = 35 | pages = 21345–21352 | date = Aug 1996 | pmid = 8702914 | doi = 10.1074/jbc.271.35.21345 | doi-access = free }}
* {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = Sep 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 | doi-access = free }}
* {{cite journal | vauthors = Shore EM, Xu M, Shah PB, Janoff HB, Hahn GV, Deardorff MA, Sovinsky L, Spinner NB, Zasloff MA, Wozney JM, Kaplan FS | title = The human bone morphogenetic protein 4 (BMP-4) gene: molecular structure and transcriptional regulation | journal = Calcified Tissue International | volume = 63 | issue = 3 | pages = 221–229 | date = Sep 1998 | pmid = 9701626 | doi = 10.1007/s002239900518 | s2cid = 8339465 }}
* {{cite journal | vauthors = Tucker AS, Matthews KL, Sharpe PT | title = Transformation of tooth type induced by inhibition of BMP signaling | journal = Science | location = New York, N.Y. | volume = 282 | issue = 5391 | pages = 1136–1138 | date = Nov 1998 | pmid = 9804553 | doi = 10.1126/science.282.5391.1136 | bibcode = 1998Sci...282.1136T }}
* {{cite journal | vauthors = Van den Wijngaard A, Pijpers MA, Joosten PH, Roelofs JM, Van zoelen EJ, Olijve W | title = Functional characterization of two promoters in the human bone morphogenetic protein-4 gene | journal = Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research | volume = 14 | issue = 8 | pages = 1432–1441 | date = Aug 1999 | pmid = 10457277 | doi = 10.1359/jbmr.1999.14.8.1432 | doi-access = free }}
* {{cite journal | vauthors = Li W, LoTurco JJ | title = Noggin is a negative regulator of neuronal differentiation in developing neocortex | journal = Developmental Neuroscience | volume = 22 | issue = 1–2 | pages = 68–73 | year = 2000 | pmid = 10657699 | doi = 10.1159/000017428 | s2cid = 35547875 }}
* {{cite journal | vauthors = Raatikainen-Ahokas A, Hytönen M, Tenhunen A, Sainio K, Sariola H | title = BMP-4 affects the differentiation of metanephric mesenchyme and reveals an early anterior-posterior axis of the embryonic kidney | journal = Developmental Dynamics : an Official Publication of the American Association of Anatomists | volume = 217 | issue = 2 | pages = 146–158 | date = Feb 2000 | pmid = 10706139 | doi = 10.1002/(SICI)1097-0177(200002)217:2<146::AID-DVDY2>3.0.CO;2-I | s2cid = 11672134 }}
* {{cite journal | vauthors = van den Wijngaard A, Mulder WR, Dijkema R, Boersma CJ, Mosselman S, van Zoelen EJ, Olijve W | title = Antiestrogens specifically up-regulate bone morphogenetic protein-4 promoter activity in human osteoblastic cells | journal = Molecular Endocrinology | location = Baltimore, Md. | volume = 14 | issue = 5 | pages = 623–633 | date = May 2000 | pmid = 10809227 | doi = 10.1210/mend.14.5.0463 | doi-access = free }}
* {{cite journal | vauthors = Ying Y, Liu XM, Marble A, Lawson KA, Zhao GQ | title = Requirement of Bmp8b for the generation of primordial germ cells in the mouse | journal = Molecular Endocrinology | location = Baltimore, Md. | volume = 14 | issue = 7 | pages = 1053–1063 | date = Jul 2000 | pmid = 10894154 | doi = 10.1210/mend.14.7.0479 | doi-access = free }}
* {{cite journal | vauthors = Nakade O, Takahashi K, Takuma T, Aoki T, Kaku T | title = Effect of extracellular calcium on the gene expression of bone morphogenetic protein-2 and -4 of normal human bone cells | journal = Journal of Bone and Mineral Metabolism | volume = 19 | issue = 1 | pages = 13–19 | year = 2001 | pmid = 11156467 | doi = 10.1007/s007740170055 | s2cid = 23873280 }}
* {{cite journal | vauthors = Hatta T, Konishi H, Katoh E, Natsume T, Ueno N, Kobayashi Y, Yamazaki T | title = Identification of the ligand-binding site of the BMP type IA receptor for BMP-4 | journal = Biopolymers | volume = 55 | issue = 5 | pages = 399–406 | year = 2001 | pmid = 11241215 | doi = 10.1002/1097-0282(2000)55:5<399::AID-BIP1014>3.0.CO;2-9 }}
* {{cite journal | vauthors = Aoki H, Fujii M, Imamura T, Yagi K, Takehara K, Kato M, Miyazono K | title = Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction | journal = Journal of Cell Science | volume = 114 | issue = Pt 8 | pages = 1483–1489 | date = Apr 2001 | pmid = 11282024 | doi = 10.1242/jcs.114.8.1483 }}
* {{cite journal | vauthors = Kalinovsky A, Boukhtouche F, Blazeski R, Bornmann C, Suzuki N, Mason CA, Scheiffele P | veditors = Polleux F | title = Development of Axon-Target Specificity of Ponto-Cerebellar Afferents | journal = Plos Biology | volume = 9 | issue = 2 | pages = e1001013 | date = Feb 2011 | pmid = 21346800 | pmc = 3035609 | doi = 10.1371/journal.pbio.1001013 | doi-access = free }}
* {{cite journal | vauthors = Cotsarelis G, Millar SE | title = Towards a molecular understanding of hair loss and its treatment | journal = Trends in Molecular Medicine | volume = 7 | issue = 7 | pages = 293–301 | date = July 2001 | pmid = 11425637 | doi = 10.1016/S1471-4914(01)02027-5 }}
* {{cite journal | vauthors = Feijen A, Goumans MJ, van den Eijnden-van Raaij AJ | title = Expression of activin subunits, activin receptors and follistatin in postimplantation mouse embryos suggests specific developmental functions for different activins | journal = Development | location = Cambridge, England | volume = 120 | issue = 12 | pages = 3621–3637 | date = December 1994 | pmid = 7821227 | doi = 10.1242/dev.120.12.3621 }}
* {{cite journal | vauthors = Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W | title = beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin | journal = Cell | volume = 105 | issue = 4 | pages = 533–545 | date = May 2001 | pmid = 11371349 | doi = 10.1016/S0092-8674(01)00336-1 | s2cid = 16775006 | doi-access = free }}
* {{cite journal | vauthors = Kulessa H, Turk G, Hogan BL | title = Inhibition of Bmp signaling affects growth and differentiation in the anagen hair follicle | journal = The EMBO Journal | volume = 19 | issue = 24 | pages = 6664–6674 | date = December 2000 | pmid = 11118201 | pmc = 305899 | doi = 10.1093/emboj/19.24.6664 }}
* {{cite journal | vauthors = Leong LM, Brickell PM | title = Bone morphogenic protein-4 | journal = The International Journal of Biochemistry & Cell Biology | volume = 28 | issue = 12 | pages = 1293–1296 | date = December 1996 | pmid = 9022288 | doi = 10.1016/S1357-2725(96)00075-1 }}
* {{cite journal | vauthors = Liem KF, Tremml G, Roelink H, Jessell TM | title = Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm | journal = Cell | volume = 82 | issue = 6 | pages = 969–979 | date = September 1995 | pmid = 7553857 | doi = 10.1016/0092-8674(95)90276-7 | s2cid = 17106597 | doi-access = free }}
* {{cite journal | vauthors = Millar SE | title = Molecular mechanisms regulating hair follicle development | journal = The Journal of Investigative Dermatology | volume = 118 | issue = 2 | pages = 216–225 | date = February 2002 | pmid = 11841536 | doi = 10.1046/j.0022-202x.2001.01670.x | doi-access = free }}
* {{cite journal | vauthors = Pourquié O, Fan CM, Coltey M, Hirsinger E, Watanabe Y, Bréant C, Francis-West P, Brickell P, Tessier-Lavigne M, Le Douarin NM | title = Lateral and axial signals involved in avian somite patterning: a role for BMP4 | journal = Cell | volume = 84 | issue = 3 | pages = 461–471 | date = February 1996 | pmid = 8608600 | doi = 10.1016/S0092-8674(00)81291-X | s2cid = 15824329 | doi-access = free }}
* {{cite journal | vauthors = Wang EA, Israel DI, Kelly S, Luxenberg DP | title = Bone morphogenetic protein-2 causes commitment and differentiation in C3H10T1/2 and 3T3 cells | journal = Growth Factors | location = Chur, Switzerland | volume = 9 | issue = 1 | pages = 57–71 | year = 1993 | pmid = 8347351 | doi = 10.3109/08977199308991582 }}
* {{cite journal | vauthors = Winnier G, Blessing M, Labosky PA, Hogan BL | title = Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse | journal = Genes & Development | volume = 9 | issue = 17 | pages = 2105–2116 | date = September 1995 | pmid = 7657163 | doi = 10.1101/gad.9.17.2105 | doi-access = free }}
{{refend}}

== External links ==
* [http://wikis.fu-berlin.de/x/R4Gq BMPedia - the Bone Morphogenetic Protein Wiki]{{dead link|date=July 2017 |bot=InternetArchiveBot |fix-attempted=yes }}
* {{UCSC genome browser|BMP4}}
* {{UCSC gene details|BMP4}}

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[[Category:Bone morphogenetic protein]]
[[Category:Developmental genes and proteins]]
[[Category:TGFβ domain]]
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