Bone morphogenetic protein 4

Source: Wikipedia, the free encyclopedia.

BMP4
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000125378

ENSMUSG00000021835

UniProt

P12644

P21275

RefSeq (mRNA)

NM_001202
NM_130850
NM_130851

NM_007554
NM_001316360

RefSeq (protein)

NP_001303289
NP_031580

Location (UCSC)n/aChr 14: 46.62 – 46.63 Mb
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Bone morphogenetic protein 4 is a protein that in humans is encoded by BMP4 gene.[4][5] BMP4 is found on chromosome 14q22-q23.

BMP4 is a member of the

transforming growth factor-beta superfamily. The 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.[6]

Discovery

Bone morphogenetic proteins were originally identified by an ability of demineralized

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.[7]

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.[8] 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 osteoinductive activity than just bmp4 alone.[9]
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

osteoblastic differentiation of mesenchymal stem cells.[citation needed
]

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.[12] In mice, loss of BMP4 results in impaired mesoderm formation.[13]

Neural Development

BMP4 plays a dorsalizing role in

Sonic hedgehog (Shh) signaling from the floor plate.[14]
It also contributes to neural crest cell apoptosis in the hindbrain region.[15]

Somites and cartilage

BMP4 is involved in somite patterning and promotes cartilage development by inducing the expression of Msx1 and Msx2 genes in the somatic mesoderm.[16][17]

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.[18] 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.[19] In lung and liver: BMP4 expression contributes to early organ specification and branching morphogenesis.

Stem cell differentiation

BMP4 synergizes with

osteogenic and chondrogenic outcomes.[20] Together, BMP4 and FGF2 can also direct differentiation toward thyroid progenitor cells.[21]

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.[22]

In the SVZ, BMP4 promotes neuronal over oligodendroglial lineage commitment via Smad4 signaling

BTG2 to promote terminal neuronal differentiation.[24]

Metabolism and adipose tissue

BMP4 plays metabolic roles by regulating

non-shivering thermogenesis.[25]

Reproductive system

In the ovary, BMP4 (in conjunction with BMP7) supports early folliculogenesis and promotes the survival of primordial follicles.[26]

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.[27]

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.

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.[28]

Smad signaling pathway

TGF-β family receptors most commonly use the

pathway is regulated by the small molecule inhibitor known as dorsomorphin which prevents the downstream effects of R-smads.[28]

Map kinase (MAPK) signaling pathways

MAPK which then induces an intracellular response.[29] 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.[29] 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.[30] 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.[30]

Generation-of-Trophoblast-Stem-Cells-from-Rabbit-Embryonic-Stem-Cells-with-BMP4-pone.0017124.s005

Inhibition

Inhibition of the BMP4 signal (by chordin, noggin, or follistatin) causes the ectoderm to differentiate into the neural plate. If these cells also receive signals from 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.[31]

It is important to note that mice in which BMP4 was completely inactivated usually died during

tooth agenesis as well as osteoporosis.[32]

Clinical significance

Increase in expression of BMP4 has been associated with a variety of bone diseases, including the heritable disorder

Fibrodysplasia Ossificans Progressiva.[33]

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.[34]

Eye development

Eyes are essential for organisms, especially 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

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 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.[35]

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 .[36] 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

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.[39]

When BMP4 is expressed ectopically, within transgenic mice the hair follicle

β-catenin as these are required in early stage morphogenesis.[40]

Other genes which can inhibit or interact with BMP4 are noggin, follistatin, gremlin, which is all expressed in the developing hair follicles.[41] In mice in which noggin is lacking, there are fewer hair follicles than on a normal mouse and the development of the 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.[9] Noggin has also been shown during in vivo experiments to induce hair growth in post natal skin.[42]

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 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.[40]

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.[38]

References

  1. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021835 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. PMID 7558046
    .
  5. PMID 7579580
    .
  6. S2CID 792305
    .
  7. ^ "Entrez Gene: BMP4 bone morphogenetic protein 4".
  8. PMID 7763240
    .
  9. ^
    S2CID 8777441
    .
  10. PMID 10749566
    .
  11. S2CID 221843254
    .
  12. PMID 7554498
    .
  13. PMID 7657163
    .
  14. PMID 9811576. Archived from the original
    on 20 May 2022. Retrieved 22 August 2021.
  15. S2CID 4361935
    .
  16. ISBN 978-0-19-870988-6
    .
  17. S2CID 16858412
    .
  18. PMID 11470817
    .
  19. PMID 12631064
    .
  20. PMID 23206696
    .
  21. PMID 26593959
    .
  22. PMID 20621052
    .
  23. PMID 18184786
    .
  24. PMID 24744701
    .
  25. PMID 30609449
    .
  26. S2CID 2141586
    .
  27. S2CID 17226774
    .
  28. ^
    PMID 19762341
    .
  29. ^ a b "Mitogen-Activated Protein Kinase Cascades". Cell Signaling Technology, Inc. Retrieved 17 November 2012.
  30. ^
    S2CID 4419607
    .
  31. S2CID 14496024
    .
  32. PMID 31128441
    .
  33. PMID 15466378
    .
  34. PMID 21331089
    .
  35. PMID 9851982
    .
  36. PMID 12117821
    .
  37. PMID 11425637
    .
  38. ^
    PMID 11841536
    .
  39. PMID 11118201
    .
  40. ^
    S2CID 16775006
    .
  41. PMID 7821227
    .
  42. S2CID 10236217
    .

Further reading

Retrieved from "https://en.wikipedia.org/w/index.php?title=Bone_morphogenetic_protein_4&oldid=1296700288"