Bone morphogenetic protein 4 antagonizes hair cell regeneration in the avian auditory epithelium.

Permanent hearing loss is often a result of damage to cochlear hair cells, which mammals are unable to regenerate. Non-mammalian vertebrates such as birds replace damaged hair cells and restore hearing function, but mechanisms controlling regeneration are not understood. The secreted protein bone morphogenetic protein 4 (BMP4) regulates inner ear morphogenesis and hair cell development. To investigate mechanisms controlling hair cell regeneration in birds, we examined expression and function of BMP4 in the auditory epithelia (basilar papillae) of chickens of either sex after hair cell destruction by ototoxic antibiotics. In mature basilar papillae, BMP4 mRNA is highly expressed in hair cells, but not in hair cell progenitors (supporting cells). Supporting cells transcribe genes encoding receptors for BMP4 (BMPR1A, BMPR1B, and BMPR2) and effectors of BMP4 signaling (ID transcription factors). Following hair cell destruction, BMP4 transcripts are lost from the sensory epithelium. Using organotypic cultures, we demonstrate that treatments with BMP4 during hair cell destruction prevent supporting cells from upregulating expression of the pro-hair cell transcription factor ATOH1, entering the cell cycle, and fully transdifferentiating into hair cells, but they do not induce cell death. By contrast, noggin, a BMP4 inhibitor, increases numbers of regenerated hair cells. These findings demonstrate that BMP4 antagonizes hair cell regeneration in the chicken basilar papilla, at least in part by preventing accumulation of ATOH1 in hair cell precursors.

Involvement of Bone Morphogenetic Proteins (BMP) in the Regulation of Ovarian Function.

Primordial germ cells migrate to the fetal gonads and proliferate during gestation to generate a fixed complement of primordial follicles, the so-called ovarian reserve. Primordial follicles comprise an oocyte arrested at the diplotene stage of meiosis, surrounded by a layer of pregranulosa cells. Activation of primordial follicles to grow beyond this arrested stage is of particular interest because, once activated, they are subjected to regulatory mechanisms involved in growth, selection, maturation, and ultimately, ovulation or atresia. The vast majority of follicles succumb to atresia and are permanently lost from the quiescent or growing pool of follicles. The bone morphogenetic proteins (BMPs), together with other intraovarian growth factors, are intimately involved in regulation of follicle recruitment, dominant follicle selection, ovulation, and atresia. Activation of primordial follicles appears to be a continuous process, and the number of small antral follicles at the beginning of the menstrual cycle provides an indirect indication of ovarian reserve. Continued antral follicle development during the follicular phase of the menstrual cycle is driven by follicle stimulating hormone (FSH) and luteinizing hormone (LH) in conjunction with many intraovarian growth factors and inhibitors interrelated in a complex web of regulatory balance. The BMP signaling system has a major intraovarian role in many species, including the human, in the generation of transcription factors that influence proliferation, steroidogenesis, cell differentiation, and maturation prior to ovulation, as well as formation of corpora lutea after ovulation. At the anterior pituitary level, BMPs also contribute to the regulation of gonadotrophin production.

The role of chordin fragments generated by partial tolloid cleavage in regulating BMP activity.

Chordin-mediated regulation of bone morphogenetic protein (BMP) family growth factors is essential in early embryogenesis and adult homoeostasis. Chordin binds to BMPs through cysteine-rich von Willebrand factor type C (vWC) homology domains and blocks them from interacting with their cell surface receptors. These domains also self-associate and enable chordin to target related proteins to fine-tune BMP regulation. The chordin-BMP inhibitory complex is strengthened by the secreted glycoprotein twisted gastrulation (Tsg); however, inhibition is relieved by cleavage of chordin at two specific sites by tolloid family metalloproteases. As Tsg enhances this cleavage process, it serves a dual role as both promoter and inhibitor of BMP signalling. Recent developments in chordin research suggest that rather than simply being by-products, the cleavage fragments of chordin continue to play a role in BMP regulation. In particular, chordin cleavage at the C-terminus potentiates its anti-BMP activity in a type-specific manner.

CRIM1, the antagonist of BMPs, is a potential risk factor of cancer.

Cysteine-rich motor neuron1 protein (CRIM1), a novel antagonist of bone morphogenetic proteins (BMPs), is reported to regulate the processing of BMPs preprotein into mature protein and the delivery of BMPs to the cell surface. Previous studies have shown that CRIM1 is an important player in regulating placental development, organogenesis, angiogenesis and kidney disease. Here, we propose that CRIM1 is a potential risk factor in cancer progression and metastasis. The epithelial-mesenchymal transition (EMT), which is characterized by the loss of epithelial phenotype and the acquisition of mesenchymal characteristics, is closely associated with invasion and metastasis of tumors. At the same time, it is hard for us to ignore the importance of angiogenesis in the genesis and progression of cancer. In this review we summarized the construction and previous researches of CRIM1. Furthermore, as it may be involved in tumor development and progression through its potential role in the EMT, capillary formation and angiogenesis maintenance, we proposed for the first time that CRIM1 may be a cancer related factor.

TGFß and BMP signaling in skeletal muscle: potential significance for muscle-related disease.

The transforming growth factor beta (TGFß) superfamily comprises a large number of secreted proteins that regulate various fundamental biological processes underlying embryonic development and the postnatal regulation of many cell types and organs. Sequence similarities define two ligand subfamilies: the TGFß/activin subfamily and the bone morphogenetic protein (BMP) subfamily. The discovery that myostatin, a member of the TGFß/activin subfamily, negatively controls muscle mass attracted attention to this pathway. However, recent findings of a positive role for BMP-mediated signaling in muscle have challenged the model of how the TGFß network regulates skeletal muscle phenotype. This review illustrates how this complex network integrates crosstalk among members of the TGFß superfamily and downstream signaling elements to regulate muscle in health and disease.

The role of BMPs in endothelial cell function and dysfunction.

The bone morphogenetic protein (BMP) family of proteins has a multitude of roles throughout the body. In embryonic development, BMPs promote endothelial specification and subsequent venous differentiation. The BMP pathway also plays important roles in the adult vascular endothelium, promoting angiogenesis and mediating shear and oxidative stress. The canonical BMP pathway functions through the Smad transcription factors; however, other intracellular signaling cascades can be activated, and receptor complexes beyond the traditional type I and type II receptors add additional layers of regulation. Dysregulated BMP signaling has been linked to vascular diseases including pulmonary hypertension and atherosclerosis. This review addresses recent advances in the roles of BMP signaling in the endothelium and how BMPs affect endothelial dysfunction and human disease.

mGLU3 metabotropic glutamate receptors modulate the differentiation of SVZ-derived neural stem cells towards the astrocytic lineage.

Neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of postnatal mice, and cultured as neurospheres, expressed functional mGlu3 receptors. Following mitogen withdrawal and plating onto poly-ornitine-coated dishes, cells dissociated from the neurospheres differentiated into GFAP(+) astrocytes (about 85%), and a small percentage of beta-III tubulin(+)-neurons and O1(+)-oligodendrocytes. Activation of mGlu3 receptors with LY379268 (100 nM, applied every other day), during the differentiation period, impaired astrocyte differentiation, favoring the maintenance in culture of proliferating progenitors co-expressing GFAP with the immature markers, Sox1 and nestin. Co-treatment with the preferential mGlu2/3 receptor antagonist, LY341495 (100 nM), reversed this effect. We examined whether mGlu3 receptors could modulate the canonical signaling pathway activated by bone morphogenic proteins (BMPs), which are known to promote astrocyte differentiation of SVZ/NSCs. An acute challenge of cells isolated from the neurospheres with BMP4 (100 ng/mL) led to phosphorylation and nuclear translocation of the transcription factors, Smads. This effect was largely attenuated by the mGlu2/3 receptor agonist, LY379268. The interaction of mGlu3 and BMP4 receptors was mediated by the activation of the mitogen-activated protein kinase (MAPK) pathway. Accordingly, LY379268 failed to affect BMP receptor signaling when combined with the MAPK kinase inhibitor, UO-126 (30 muM). These data raise the intriguing possibility that glutamate regulates differentiation of SVZ/NSCs by activating mGlu3 receptors.

Bone morphogenetic protein 7 (BMP-7) increases the expression of follicle-stimulating hormone (FSH) receptor in human granulosa cells.

OBJECTIVE: To examine the effect of bone morphogenetic protein 7 (BMP-7) on FSH receptor (FSHR) expression in human granulosa cells. DESIGN: Laboratory study using human samples. SETTING: University hospital. PATIENT(S): Human granulosa cells were obtained from 60 women undergoing oocyte retrieval for IVF. INTERVENTION(S): Human granulosa cells (GCs) were cultured with recombinant BMP-7, followed by RNA extraction. MAIN OUTCOME MEASURE(S): mRNA levels of GCs were measured by real-time reverse-transcription polymerase chain reaction. RESULT(S): Bone morphogenetic protein 7 increased FSHR gene expression in human luteinized granulosa cells, whereas it decreased LH receptor gene expression. Bone morphogenetic protein 7 also increased FSH-induced cyclic adenosine monophosphate production in GCs, indicating up-regulation of the cellular response to FSH. Although BMP-7 increased gene expression of activin-betaA and -betaB in GCs, inhibition of activin function did not affect the BMP-7-induced FSHR gene expression. CONCLUSION(S): These findings provide new insight into the biologic function of BMP-7 in the human ovary and demonstrate its unique mechanism of regulating FSHR action.

Sequential roles for myosin-X in BMP6-dependent filopodial extension, migration, and activation of BMP receptors.

Endothelial cell migration is an important step during angiogenesis, and its dysregulation contributes to aberrant neovascularization. The bone morphogenetic proteins (BMPs) are potent stimulators of cell migration and angiogenesis. Using microarray analyses, we find that myosin-X (Myo10) is a BMP target gene. In endothelial cells, BMP6-induced Myo10 localizes in filopodia, and BMP-dependent filopodial assembly decreases when Myo10 expression is reduced. Likewise, cellular alignment and directional migration induced by BMP6 are Myo10 dependent. Surprisingly, we find that Myo10 and BMP6 receptor ALK6 colocalize in a BMP6-dependent fashion. ALK6 translocates into filopodia after BMP6 stimulation, and both ALK6 and Myo10 possess intrafilopodial motility. Additionally, Myo10 is required for BMP6-dependent Smad activation, indicating that in addition to its function in filopodial assembly, Myo10 also participates in a requisite amplification loop for BMP signaling. Our data indicate that Myo10 is required to guide endothelial migration toward BMP6 gradients via the regulation of filopodial function and amplification of BMP signals.