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BMP4 in eye development Eyes are essential for organisms, especially terrestrial vertebrates, to observe prey and obstacle; this is critical for their survivals. The formation of the eyes starts as optic vesicles and lens derived from the neuroectoderm. Bone morphogenic proteins are known to stimulate the lens formation of the Eyes. 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 (Y.Furuta and B.L.M Hogan, 1998). This concentration gradient of BMP4 in optic vesicle is critical for lens induction. Researcher, Dr. Furuta and Dr. Hogan (1998), found out that if they did a laser mutation on mice embryos and causing a BMP4¬tm1 homozygous null mutation, this embryo will not develop the lens (Y.Furuta and B.L.M Hogan, 1998). They also did an in situ 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 vesicle of the mice embryos (Y.Furuta and B.L.M Hogan, 1998). 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 (Y.Furuta and B.L.M Hogan, 1998). 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 (Y.Furuta and B.L.M Hogan, 1998). Present and future studies: Recently, researchers found that injection of Noggin into lens fiber cells in mice would significantly reduce the BMP4 proteins in the cells (S.C. Faber, el al.). 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 (S.C. Faber, el al.). However, there are still a lot of unknown about the mechanism of inhibition on BMP4 and downstream regulation of Sox2. In the future, researchers is 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.

Reference: 1.	Xu, J., & Zhu, D. (2012). Over-expression of bmp4 inhibits experimental choroidal neovascularization by modulating vegf and mmp-9. 15, 213-227. 2.	Faber, S. C. (2002). Bmp signaling is required for development of primary lens fiber cells. 129, 3727-3737. 3.	Fueuta, Y. F., B.L.M Hogan, (1998). Bmp4 is essential for lens induction in the mouse embryo. 12, 3764-3775.

BMP4

BMP4 is found to have been mapped on chromosome 14q22-q23. 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. (1) 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. (2) As of yet not much is known about how BMPS interact with the extracellular matrix. As well little is known about the pathways which then degrade BMP4.

Bone morphogenic proteins are known to stimulate bone formation in adult animals. This is thought that inducing osteoblastic commitment and differentiation of stem cells such as mesenchymal s.cells. (3) In embryonic development bmps are known to play a large role in embryonic development. In the embryo BMP4 helps establish dorsal-ventral axis formation in xenopus through inducing ventral mesoderm. In mice targets inactivation of BMP4 disrupts mesoderm from forming. (4) As well establishes dorsal-ventral patterning of the developing neural tube with the help of BMP7, and inducing dorsal characters. (5)

BMP4 also limits the extent to which neural differentiation in xenopus embryos occurs by inducing epidermis. (1) They can aid in inducing the lateral characteristics in somites. Somites are required for the development of things such as muscles within limbs. (6) BMP4 helps in the patterning of the developing head though inducing apoptosis of the neural crest cells; this is done in the hindbrain. (7)

BMP4 is also involved in other such events such as tooth development, modulating skeletal shape, interdigit apoptosis in developing limbs, eye formation, and inhibiting hair development. (1) It is important to note that mice in which BMP4 was inactivated usually died during the event of gastrulating. It is thought that inactivation of human BMP4 would likely have the same effect. However, mutations which are subtle in humans could also have subtle effects phenotypically. (1)

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. (8) The cycles of hair follicles are that of growth, or anagen, regression or catagen, and rest or telogen. (9) In mammals reciprocal epithelial and mesynchymal interactions control the development of hair. Genes such as BMP4 and 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. (10) 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, and 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, and B-catenin as these are required in early stage morphogenesis. (11) Other genes which can inhibit or interact with BMP4 are noggin, follistatin, gremlin, which is all expressed in the developing hair follicles. (12) 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. (13) 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 though restricting growth factor expression in the hair matrix and antagonism between growth and differentiation signaling. (11) New research Understanding how BMP4 regulates hair developing is essential in curing alopecia. 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. It is important to keep in mind the control of dosage, how these pathways are modified, and preventing serious harmful effects that have long term consequences. Understanding how BMP4 works in preventing hair loss is still an active area of research. (7) References 1.	Aono, A., Hazama, M., Notoya, K., Taketomi, S., Yamasaki, H., Tsukuda, R., Sasaki, S., et al. (1995). Potent ectopic bone-inducing activity of bone morphogenetic protein-4/7 heterodimer. Biochemical and Biophysical Research Communications, 210(3), 670-677. Elsevier. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7763240 2.	Botchkarev, V. A., Botchkareva, N. V., Roth, W., Nakamura, M., Chen, L. H., Herzog, W., Lindner, G., et al. (1999). Noggin is a mesenchymally derived stimulator of hair-follicle induction. Nature Cell Biology, 1(3), 158-164. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10559902 3.	Cotsarelis, G., & Millar, S. E. (2001). Towards a molecular understanding of hair loss and its treatment. Trends in Molecular Medicine, 7(7), 293-301. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11425637 4.	Feijen, A., Goumans, M. J., & Van Den Eijnden-van Raaij, A. J. (1994). Expression of activin subunits, activin receptors and follistatin in postimplantation mouse embryos suggests specific developmental functions for different activins. Development Cambridge England, 120(12), 3621-3637. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7821227 5.	Graham, A., Francis-West, P., Brickell, P., & Lumsden, A. (1994). The signalling molecule BMP4 mediates apoptosis in the rhombencephalic neural crest. Nature, 372(6507), 684-686. Nature Publishing Group. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7990961 6.	Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G., & Birchmeier, W. (2001). beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell, 105(4), 533-545. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11371349 7.	Kulessa, H., Turk, G., & Hogan, B. L. M. (2000). Inhibition of Bmp signaling affects growth and differentiation in the anagen hair follicle. the The European Molecular Biology Organization Journal, 19(24), 6664-6674. Oxford University Press. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=305899&tool=pmcentrez&rendertype=abstract 8.	Leong, L. M., & Brickell, P. M. (1996). Bone morphogenic protein-4. The International Journal of Biochemistry Cell Biology, 28(12), 1293-1296. Academic Press. doi:10.1089/cbr.2010.0857 9.	Liem, K. F., Tremml, G., Roelink, H., & Jessell, T. M. (1995). Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell, 82(6), 969-979. Elsevier. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7553857 10.	Millar, Sarah E. (2002). Molecular mechanisms regulating hair follicle development. The Journal of investigative dermatology, 118(2), 216-225. Nature Publishing Group. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11841536 11.	Pourquié, O., Fan, C. M., Coltey, M., Hirsinger, E., Watanabe, Y., Bréant, C., Francis-West, P., et al. (1996). Lateral and axial signals involved in avian somite patterning: a role for BMP4. Cell, 84(3), 461-471. Cell Press. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8608600 12.	Wang, E. A., Israel, D. I., Kelly, S., & Luxenberg, D. P. (1993). Bone Morphogenetic Protein-2 Causes Commitment and Differentiation in C3Hl0T1/2 and 3T3 Cells. Growth Factors, 9(1), 57-71. Informa Healthcare. doi:10.3109/08977199308991582 13.	Winnier, G., Blessing, M., Labosky, P. A., & Hogan, B. L. (1995). Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes & Development, 9(17), 2105-2116. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7657163