Bone morphogenetic protein 4

BMP4 is a member of the bone morphogenetic protein family which is part of the transforming growth factor-beta superfamily.

BMP4 is found in early embryonic development in the ventral marginal zone and in the eye, heart blood and otic vesicle.

This particular family member plays an important role in the onset of endochondral bone formation in humans.

In the embryo BMP4 helps establish dorsal-ventral axis formation in Xenopus frog through inducing ventral mesoderm.

[11] In adult, BMP4 is important for the neurogenesis (i.e., the generation of new neurons) that occurs throughout life in two neurogenic niches of the brain, the dentate gyrus of the hippocampus and the subventricular zone (SVZ) adjacent to lateral ventricles.

[12] In the SVZ, BMP-mediated signaling via Smad4 is required to initiate neurogenesis from adult neural stem cells and suppress the alternative fate of oligodendrogliogenesis.

Limb bud regulation and development of the lungs, liver, teeth and facial mesenchyme cells are other important functions attributed to BMP4 signaling.

BMP4 also plays important roles in adipose tissue: it is essential for white adipogenesis, and promotes adipocyte differentiation.

Upon gastrulation, the transcription of BMP4 is limited to the ventrolateral marginal zone due to inhibition from the dorsalizing side of the developing embryo.

[22] BMP4 has been shown to induce the expression of the Msx gene family, which is believed to be part of cartilage formation from somitic mesoderm.

Inhibition of the BMP4 signal (by chordin, noggin, or follistatin) causes the ectoderm to differentiate into the neural plate.

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.

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.

[29] 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.

[30] Signal transduction via these receptors occurs via Smad and map kinase pathways to effect transcription of its target genes.

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

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.

[32] Increase in expression of BMP4 has been associated with a variety of bone diseases, including the heritable disorder Fibrodysplasia Ossificans Progressiva.

[34] Eyes are essential for organisms, especially terrestrial vertebrates, to observe prey and obstacles; this is critical for their survival.

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.

[39] When BMP4 is expressed ectopically, within transgenic mice the hair follicle outer root sheath (ORS) the proliferation of the cell matrix is inhibited.

Other important factors to consider in the development of hair is the expression of Shh (sonic hedgehog), BMP7, BMP2, WNT, and 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.

In chick embryos it is shown that ectopically expressed noggin produces enlarged follicles, and BMP4 signaling shows repressed placode fate in nearby cells.

[26] Noggin has also been shown during in vivo experiments to induce hair growth in post natal skin.

BMP4 signal transduction pathway. The Smad and the MAPK signal transduction pathways are used by BMP4 in order to alter transcription of its target genes.
Generation-of-Trophoblast-Stem-Cells-from-Rabbit-Embryonic-Stem-Cells-with-BMP4-pone.0017124.s005