BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb

Development ◽  
2001 ◽  
Vol 128 (22) ◽  
pp. 4449-4461 ◽  
Author(s):  
Kyung Ahn ◽  
Yuji Mishina ◽  
Mark C. Hanks ◽  
Richard R. Behringer ◽  
E. Bryan Crenshaw
Keyword(s):  
Limb Development ◽  
Apical Ectodermal Ridge ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Limb Bud ◽  
Gene Encoding ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Embryonic Limb

We demonstrate that signaling via the bone morphogenetic protein receptor IA (BMPR-IA) is required to establish two of the three cardinal axes of the limb: the proximal-distal axis and the dorsal-ventral axis. We generated a conditional knockout of the gene encoding BMPR-IA (Bmpr) that disrupted BMP signaling in the limb ectoderm. In the most severely affected embryos, this conditional mutation resulted in gross malformations of the limbs with complete agenesis of the hindlimbs. The proximal-distal axis is specified by the apical ectodermal ridge (AER), which forms from limb ectoderm at the distal tip of the embryonic limb bud. Analyses of the expression of molecular markers, such as Fgf8, demonstrate that formation of the AER was disrupted in the Bmpr mutants. Along the dorsal/ventral axis, loss of engrailed 1 (En1) expression in the non-ridge ectoderm of the mutants resulted in a dorsal transformation of the ventral limb structures. The expression pattern of Bmp4 and Bmp7 suggest that these growth factors play an instructive role in specifying dorsoventral pattern in the limb. This study demonstrates that BMPR-IA signaling plays a crucial role in AER formation and in the establishment of the dorsal/ventral patterning during limb development.

Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis

10.1038/88919 ◽  
2001 ◽  
Vol 28 (2) ◽  
pp. 184-187 ◽  
Author(s):  
James R. Howe ◽  
Jennifer L. Bair ◽  
Mohamed G. Sayed ◽  
Mary E. Anderson ◽  
Frank A. Mitros ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Germline Mutations ◽  
Juvenile Polyposis ◽  
Gene Encoding ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein

scholarly journals Bone morphogenetic protein receptor 2 inhibition destabilizes microtubules promoting the activation of lysosomes and cell death of lung cancer cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Arindam Mondal ◽  
Rachel NeMoyer ◽  
Mehul Vora ◽  
Logan Napoli ◽  
Zoya Syed ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Survival ◽  
Cancer Cells ◽  
Bone Morphogenetic Protein ◽  
Neurological Diseases ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein

Abstract Background Recent studies have shown that bone morphogenetic protein receptor 2 (BMPR2) regulates cell survival signaling events in cancer cells independent of the BMP type 1 receptor (BMPR1) or the Smad-1/5 transcription factor. Mutations in BMPR2 trafficking proteins leads to overactive BMP signaling, which leads to neurological diseases caused by BMPR2 stabilization of the microtubules. It is not known whether BMPR2 regulates the microtubules in cancer cells and what effect this has on cell survival. It is also not known whether alterations in BMPR2 trafficking effects activity and response to BMPR2 inhibitors. Methods We utilized BMPR2 siRNA and the BMP receptor inhibitors JL5 and Ym155, which decrease BMPR2 signaling and cause its mislocalization to the cytoplasm. Using the JL5 resistant MDA-MD-468 cell line and sensitive lung cancer cell lines, we examined the effects of BMPR2 inhibition on BMPR2 mislocalization to the cytoplasm, microtubule destabilization, lysosome activation and cell survival. Results We show that the inhibition of BMPR2 destabilizes the microtubules. Destabilization of the microtubules leads to the activation of the lysosomes. Activated lysosomes further decreases BMPR2 signaling by causing it to mislocalizated to the cytoplasm and/or lysosome for degradation. Inhibition of the lysosomes with chloroquine attenuates BMPR2 trafficking to the lysosome and cell death induced by BMPR2 inhibitors. Furthermore, in MDA-MD-468 cells that are resistant to JL5 induced cell death, BMPR2 was predominately located in the cytoplasm. BMPR2 failed to localize to the cytoplasm and/or lysosome following treatment with JL5 and did not destabilize the microtubules or activate the lysosomes. Conclusions These studies reveal that the inhibition of BMPR2 destabilizes the microtubules promoting cell death of cancer cells that involves the activation of the lysosomes. Resistance to small molecules targeting BMPR2 may occur if the BMPR2 is localized predominantly to the cytoplasm and/or fails to localize to the lysosome for degradation.

scholarly journals Bone morphogenetic protein-4 and bone morphogenetic protein receptors expressions in the adult rat eye

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Yuka Maruyama-Koide ◽  
Sumiko Mikawa ◽  
Takeshi Sasaki ◽  
Kohji Sato
Keyword(s):  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein 4 ◽  
Basal Cells ◽  
Photoreceptor Layer ◽  
Bone Morphogenetic Protein Receptor ◽  
Adult Rat ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Protein Receptors

<p>We investigated the expressions of bone morphogenetic protein-4 (BMP4) and its receptors, bone morphogenetic protein receptor IA (BMPRIA), bone morphogenetic protein receptor IB (BMPRIB) and bone morphogenetic protein receptor II (BMPRII) in the adult rat eye. Interesting differences in expression profile were observed between BMPRIA and BMPRIB in the retina. BMPRIA-like immunoreactivity (IR) was very intensely seen in the photoreceptor layer, while BMPRIB-IR was mainly observed in the other layers. In the cornea, BMP4, BMPRIA, BMPRIB and BMPRII-IRs were abundantly seen in the cell body of basal cells in the corneal epithelium, and endothelium. In the lens, BMP4, BMPRIA, BMPRIB and BMPRII-IRs were observed in epithelial cells, lens cortical fiber cells, however they were not seen in the capsule and the central region of the lens. In the iris and ciliary body, strong BMP4 and BMPRIB-IRs were observed in nonpigmented epithelium. These results suggest that different kinds of BMP signaling should be needed in different areas in the adult eye to keep the shapes, differentiation levels, and functions of various cells.<strong></strong></p>

scholarly journals The role of genomics and genetics in pulmonary arterial hypertension

2020 ◽  
Vol 2020 (1) ◽  
Author(s):  
Emilia M Swietlik ◽  
Stefan Gräf ◽  
Nicolas W Morrell
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Gene Encoding ◽  
New Era ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial

[No abstract. Showing first paragraph of article]Although pulmonary hypertension (PH) had been recognised for centuries, it was not until the invention of cardiac catheterisation in the 1950s that enabled an accurate gene encoding bone morphogenetic protein receptor type 2, in patients with familial and clinical diagnosis. The discovery of heterozygous germline mutations in BMPR2, the idiopathic forms of pulmonary arterial hypertension (PAH) was another breakthrough in understanding the disease and initiated a new era in care of patients with this condition.

Products, genetic linkage and limb patterning activity of a murine hedgehog gene

Development ◽  
1994 ◽  
Vol 120 (11) ◽  
pp. 3339-3353 ◽  
Author(s):  
D.T. Chang ◽  
A. Lopez ◽  
D.P. von Kessler ◽  
C. Chiang ◽  
B.K. Simandl ◽  
...  
Keyword(s):  
Limb Development ◽  
Genetic Linkage ◽  
Pcr Primers ◽  
Amino Acid Identity ◽  
Protein Product ◽  
Proteolytic Processing ◽  
Limb Bud ◽  
Gene Encoding ◽  
Mouse Limb ◽  
Drosophila Embryos

The hedgehog (hh) segmentation gene of Drosophila melanogaster encodes a secreted signaling protein that functions in the patterning of larval and adult structures. Using low stringency hybridization and degenerate PCR primers, we have isolated complete or partial hh-like sequences from a range of invertebrate species including other insects, leech and sea urchin. We have also isolated three mouse and two human DNA fragments encoding distinct hh-like sequences. Our studies have focused upon Hhg-1, a mouse gene encoding a protein with 46% amino acid identity to hh. The Hhg-1 gene, which corresponds to the previously described vhh-1 or sonic class, is expressed in the notochord, ventral neural tube, lung bud, hindgut and posterior margin of the limb bud in developing mouse embryos. By segregation analysis the Hhg-1 gene has been localized to a region in proximal chromosome 5, where two mutations affecting mouse limb development previously have been mapped. In Drosophila embryos, ubiquitous expression of the Hhg-1 gene yields effects upon gene expression and cuticle pattern similar to those observed for the Drosophila hh gene. We also find that cultured quail cells transfected with a Hhg-1 expression construct can induce digit duplications when grafted to anterior or mid-distal but not posterior borders within the developing chick limb; more proximal limb element duplications are induced exclusively by mid-distal grafts. Both in transgenic Drosophila embryos and in transfected quail cells, the Hhg-1 protein product is cleaved to yield two stable fragments from a single larger precursor. The significance of Hhg-1 genetic linkage, patterning activity and proteolytic processing in Drosophila and chick embryos is discussed.

scholarly journals Identification of a Lysosomal Pathway Regulating Degradation of the Bone Morphogenetic Protein Receptor Type II

2010 ◽  
Vol 285 (48) ◽  
pp. 37641-37649 ◽  
Author(s):  
Hannah J. Durrington ◽  
Paul D. Upton ◽  
Simon Hoer ◽  
Jessica Boname ◽  
Benjamin J. Dunmore ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Receptor Type ◽  
Type Ii ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein

scholarly journals Case study of a Hungarian breeding program using imported Booroola rams

2004 ◽  
Vol 47 (4) ◽  
pp. 359-366
Author(s):  
M. Árnyasi ◽  
A. Zsolnai ◽  
I. Komlósi ◽  
L. Fésüs ◽  
A. Jávor
Keyword(s):  
Major Gene ◽  
Ovulation Rate ◽  
Dna Testing ◽  
Bone Morphogenetic Protein Receptor ◽  
Long Period ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Pcr Rflp ◽  
Phenotype Measurement

Abstract. The first major gene for prolificacy identified in sheep was the Booroola (FecB) gene. Since the recognition of its existence, the Booroola Merino has spread all over the world. In Hungary, a new breed – called Hungarian Prolific Merino – had been established based on the crossing of Hungarian Merino ewes and Booroola Merino rams, and was acknowledged in 1992. The only way to determine the FecB genotypes has been the measurement of the ovulation rate over a long period. In 2001, the Booroola mutation was identified. Mutation on the bone morphogenetic protein receptor – 1B gene was found to be associated with the increased ovulation rate in the Booroola Merino ewes. 138 ewes and 46 rams in the Hungarian Prolific Merino population were tested for this mutation by PCR-RFLP and their FecB genotypes were determined. One copy of the FecB allele increased (P < 0,05) the ovulation rate by 0.89 ova and two copies increased by an average of 2.27 ova. Effectiveness of the FecB genotype estimation based on phenotype measurement was also compared to the results of direct DNA testing, and was found to have up to 80% accuracy.

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