scholarly journals Caenorhabditis elegans BMP Transcriptional Program Implicates Collagen Genes in Body Size Regulation

2017 ◽  
Author(s):  
Uday Madaan ◽  
Edlira Yzeiraj ◽  
Michael Meade ◽  
Christine A. Rushlow ◽  
Cathy Savage-Dunn
Keyword(s):  
Body Size ◽  
Caenorhabditis Elegans ◽  
Signaling Pathway ◽  
Transcriptional Network ◽  
Bmp Signaling ◽  
Functional Impairments ◽  
Size Regulation ◽  
Downstream Effectors ◽  
Bmp Pathway ◽  
Collagen Genes

AbstractBody size is a tightly regulated phenotype in metazoans that is dependent on both intrinsic and extrinsic factors. While signaling pathways such as insulin, Hippo, and myostatin are known to control organ and body size, the downstream effectors that mediate their effects are still poorly understood. In the nematode C. elegans, a Bone Morphogenetic Protein (BMP)-related signaling pathway is the major regulator of growth and body size. DBL-1, the BMP-related ligand, is secreted by neurons and body wall muscle, and acts as a dose-dependent regulator of body size. We investigated the transcriptional network through which the DBL-1/BMP pathway regulates body size and identified cuticle collagen genes as major effectors of growth control. Here we demonstrate that cuticle collagen genes can act as positive regulators (col-41), dose-sensitive regulators (rol-6), and negative regulators (col-141, col-142) of body size. Moreover, we show requirement of DBL-1/BMP signaling for stage-specific expression of cuticle collagen genes. We used chromatin immunoprecipitation followed by high throughput sequencing (ChIP-Seq) and electrophoretic mobility shift assays to show that the Smad signal transducers directly associate with conserved Smad binding elements in regulatory regions of col-141 and col-142, but not of col-41. Hence, cuticle collagen genes are directly and indirectly regulated via the DBL-1/BMP pathway. These results provide the first direct regulatory link between this conserved signaling pathway and the collagen genes that act as its downstream effectors in body size regulation. Since collagen mutations and misregulation are implicated in numerous human genetic disorders and injury sequelae, understanding how collagen gene expression is regulated has broad implications.Author SummaryBody size in humans and other animals is determined by the combined influence of genetic and environmental factors. Failure to regulate growth and body size appropriately can lead to a variety of functional impairments and reduced fitness. Progress has been made in identifying genetic determinants of body size, but these have not often been connected into functional pathways. In the nematode model Caenorhabditis elegans, single gene mutations in the BMP signaling pathway have profound effects on body size. Here we have elucidated the BMP transcriptional network and identified cuticle collagen genes as downstream effectors of body size regulation through the BMP pathway. Collagens play diverse roles in biology; mutations are often associated with rare heritable diseases such as osteogenesis imperfecta and Ehlers-Danlos syndrome. Our work thus connects a conserved signaling pathway with its critical downstream effectors, advancing insight into how body size is specified.

scholarly journals lon-1 Regulates Caenorhabditis elegans Body Size Downstream of the dbl-1 TGFβ Signaling Pathway

2002 ◽  
Vol 246 (2) ◽  
pp. 418-428 ◽  
Author(s):  
Lisa L. Maduzia ◽  
Tina L. Gumienny ◽  
Cole M. Zimmerman ◽  
Huang Wang ◽  
Pradnya Shetgiri ◽  
...  
Keyword(s):  
Body Size ◽  
Caenorhabditis Elegans ◽  
Signaling Pathway ◽  
Tgfβ Signaling ◽  
Tgfβ Signaling Pathway

scholarly journals crm-1 facilitates BMP signaling to control body size in Caenorhabditis elegans

2007 ◽  
Vol 311 (1) ◽  
pp. 95-105 ◽  
Author(s):  
Wong Yan Fung ◽  
Ko Frankie Chi Fat ◽  
Cheah Kathryn Song Eng ◽  
Chow King Lau
Keyword(s):  
Body Size ◽  
Caenorhabditis Elegans ◽  
Bmp Signaling ◽  
Control Body

scholarly journals BMP Signaling Determines Body Size via Transcriptional Regulation of Collagen Genes inCaenorhabditis elegans

Genetics ◽  
2018 ◽  
Vol 210 (4) ◽  
pp. 1355-1367 ◽  
Author(s):  
Uday Madaan ◽  
Edlira Yzeiraj ◽  
Michael Meade ◽  
James F. Clark ◽  
Christine A. Rushlow ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Body Size ◽  
Bmp Signaling ◽  
Collagen Genes

scholarly journals The C. elegans SMOC-1 protein acts cell non-autonomously to promote bone morphogenetic protein signaling

2018 ◽  
Author(s):  
Melisa S. DeGroot ◽  
Herong Shi ◽  
Alice Eastman ◽  
Alexandra N. McKillop ◽  
Jun Liu
Keyword(s):  
Body Size ◽  
Bone Morphogenetic Protein ◽  
Calcium Binding ◽  
Binding Protein ◽  
Calcium Binding Protein ◽  
Bmp Signaling ◽  
C Elegans ◽  
Morphogenetic Protein ◽  
Positive Modulator ◽  
Bmp Pathway

ABSTRACTBone morphogenetic protein (BMP) signaling regulates many different developmental and homeostatic processes in metazoans. The BMP pathway is conserved in Caenorhabditis elegans, and is known to regulate body size and mesoderm development. We have identified the C. elegans smoc-1 (Secreted MOdular Calcium binding protein-1) gene as a new player in the BMP pathway. smoc-1(0) null mutants have a small body size, while overexpression of smoc-1 led to a long body size and increased expression of the RAD-SMAD BMP reporter, suggesting that SMOC-1 acts as a positive modulator of BMP signaling. Using double mutant analysis, we showed that SMOC-1 antagonizes the function of the glypican LON-2 and acts through the BMP ligand DBL-1 to regulate BMP signaling. Moreover, SMOC-1 appears to specifically regulate BMP signaling without significant involvement in a TGFβ-like pathway that regulates dauer development. We found that smoc-1 is expressed in multiple tissues, including cells of the pharynx, intestine, and posterior hypodermis, and that the expression of smoc-1 in the intestine is positively regulated by BMP signaling. We further established that SMOC-1 functions cell non-autonomously to regulate body size. Human SMOC1 and SMOC2 can each partially rescue the smoc-1(0) mutant phenotype, suggesting that SMOC-1’s function in modulating BMP signaling is evolutionarily conserved. Together, our findings highlight a conserved role of SMOC proteins in modulating BMP signaling in metazoans.ARTICLE SUMMARYBMP signaling is critical for development and homeostasis in metazoans, and is under tight regulation. We report the identification and characterization of a Secreted MOdular Calcium binding protein SMOC-1 as a positive modulator of BMP signaling in C. elegans. We established that SMOC-1 antagonizes the function of LON-2/glypican and acts through the DBL-1/BMP ligand to promote BMP signaling. We identified smoc-1-expressing cells, and demonstrated that SMOC-1 acts cell non-autonomously and in a positive feedback loop to regulate BMP signaling. We also provide evidence suggesting that the function of SMOC proteins in the BMP pathway is conserved from worms to humans.

scholarly journals The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity

2007 ◽  
Vol 104 (3) ◽  
pp. 840-845 ◽  
Author(s):  
John E. Pimanda ◽  
Ian J. Donaldson ◽  
Marella F. T. R. de Bruijn ◽  
Sarah Kinston ◽  
Kathy Knezevic ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transcriptional Network ◽  
Bmp Signaling

scholarly journals Akirin Is Required for Muscle Function and Acts Through the TGF-β Sma/Mab Signaling Pathway in Caenorhabditis elegans Development

2019 ◽  
Vol 10 (1) ◽  
pp. 387-400 ◽  
Author(s):  
Richard Bowman ◽  
Nathan Balukoff ◽  
Amy Clemons ◽  
Emily Koury ◽  
Talitha Ford ◽  
...  
Keyword(s):  
Body Size ◽  
Caenorhabditis Elegans ◽  
Signaling Pathway ◽  
Chromatin Remodeling ◽  
Muscle Development ◽  
The Body ◽  
Model Systems ◽  
Loss Of Function ◽  
C Elegans ◽  
Chromatin Remodeling Complex

Akirin, a conserved metazoan protein, functions in muscle development in flies and mice. However, this was only tested in the rodent and fly model systems. Akirin was shown to act with chromatin remodeling complexes in transcription and was established as a downstream target of the NFκB pathway. Here we show a role for Caenorhabditis elegans Akirin/AKIR-1 in the muscle and body length regulation through a different pathway. Akirin localizes to somatic tissues throughout the body of C. elegans, including muscle nuclei. In agreement with its role in other model systems, Akirin loss of function mutants exhibit defects in muscle development in the embryo, as well as defects in movement and maintenance of muscle integrity in the C. elegans adult. We also have determined that Akirin acts downstream of the TGF-β Sma/Mab signaling pathway in controlling body size. Moreover, we found that the loss of Akirin resulted in an increase in autophagy markers, similar to mutants in the TGF-β Sma/Mab signaling pathway. In contrast to what is known in rodent and fly models, C. elegans Akirin does not act with the SWI/SNF chromatin-remodeling complex, and is instead involved with the NuRD chromatin remodeling complex in both movement and regulation of body size. Our studies define a novel developmental role (body size) and a new pathway (TGF-β Sma/Mab) for Akirin function, and confirmed its evolutionarily conserved function in muscle development in a new organism.

scholarly journals Aberrant BMP2 Signaling in Patients Diagnosed with Osteoporosis

2020 ◽  
Vol 21 (18) ◽  
pp. 6909 ◽  
Author(s):  
Hilary W. Durbano ◽  
Daniel Halloran ◽  
John Nguyen ◽  
Victoria Stone ◽  
Sean McTague ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein 2 ◽  
Osteoblast Activity ◽  
Morphogenetic Protein ◽  
Osteogenic Response ◽  
Type Ia ◽  
Bmp Pathway ◽  
Negative Side Effects ◽  
Potent Growth

The most common bone disease in humans is osteoporosis (OP). Current therapeutics targeting OP have several negative side effects. Bone morphogenetic protein 2 (BMP2) is a potent growth factor that is known to activate both osteoblasts and osteoclasts. It completes these actions through both SMAD-dependent and SMAD-independent signaling. A novel interaction between the BMP type Ia receptor (BMPRIa) and casein kinase II (CK2) was discovered, and several CK2 phosphorylation sites were identified. A corresponding blocking peptide (named CK2.3) was designed to further elucidate the phosphorylation site’s function. Previously, CK2.3 demonstrated an increased osteoblast activity and decreased osteoclast activity in a variety of animal models, cell lines, and isolated human osteoblasts. It is hypothesized that CK2.3 completes these actions through the BMP signaling pathway. Furthermore, it was recently discovered that BMP2 did not elicit an osteogenic response in osteoblasts from patients diagnosed with OP, while CK2.3 did. In this study, we explore where in the BMP pathway the signaling disparity or defect lies in those diagnosed with OP. We found that osteoblasts isolated from patients diagnosed with OP did not activate SMAD or ERK signaling after BMP2 stimulation. When OP osteoblasts were stimulated with BMP2, both BMPRIa and CK2 expression significantly decreased. This indicates a major disparity within the BMP signaling pathway in patients diagnosed with osteoporosis.

scholarly journals Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 688-695 ◽  
Author(s):  
Jaroslav Truksa ◽  
Pauline Lee ◽  
Ernest Beutler
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Bone Morphogenetic Proteins ◽  
Binding Sites ◽  
Iron Homeostasis ◽  
Bmp Signaling ◽  
Physical Association ◽  
Maximal Activation ◽  
Bmp Pathway ◽  
Responsive Element

Abstract Hepcidin plays a major role in the regulation of iron homeostasis. Several bone morphogenetic proteins (BMPs) are strong inducers of hepcidin (Hamp1, HAMP) expression. Hemojuvelin, a protein critical for maintaining appropriate levels of hepcidin, acts as a coreceptor for BMP2 and BMP4, thereby providing a link between iron homeostasis and the BMP-signaling pathway. We show that a robust BMP, hemojuvelin, and SMAD1 response by murine Hamp1 is dependent on a distal BMP responsive element (BMP-RE2), the adjacent bZIP, HNF4α/COUP binding sites, and plus or minus 50 bp of the flanking area within −1.6 to −1.7 kb of the Hamp1 promoter. Furthermore, the STAT site and the BMP responsive element (BMP-RE1) located in the proximal 260-bp region of the Hamp1 promoter are also indispensable for maximal activation of hepcidin transcription. The homologous motifs in the distal and proximal regions of the human HAMP promoter act in a manner similar to the murine Hamp1 promoter. Therefore, we propose that the regulation of hepcidin by the BMP pathway involves the formation of a complex of liver-specific and response-specific transcription factors bound to the distal BMP-RE2 /bZIP/HNF4α/COUP region and to the proximal BMP-RE1/STAT region possibly by physical association of the 2 regions.

scholarly journals Feedback regulation of BMP signaling by C. elegans cuticle collagens

2019 ◽  
Author(s):  
Uday Madaan ◽  
Lionel Faure ◽  
Albar Chowdhury ◽  
Shahrear Ahmed ◽  
Emma J. Ciccarelli ◽  
...  
Keyword(s):  
Body Size ◽  
Regulation Of Gene Expression ◽  
Feedback Regulation ◽  
Bmp Signaling ◽  
Physical Separation ◽  
C Elegans ◽  
Morphogenetic Protein ◽  
Cellular Responsiveness ◽  
Collagen Genes ◽  
Cuticle Collagens

AbstractCellular responsiveness to environmental cues, including changes in extracellular matrix (ECM), is critical for normal processes such as development and wound healing, but can go awry, as in oncogenesis and fibrosis. One type of molecular pathway allowing this responsiveness is the bone morphogenetic protein (BMP) signaling pathway. Due to their broad and potent functions, BMPs and their signaling pathways are highly regulated at multiple levels. In Caenorhabditis elegans, the BMP ligand DBL-1 is a major regulator of body size. We have previously shown that DBL-1/BMP signaling determines body size through transcriptional regulation of cuticle collagen genes. We have now obtained evidence of feedback regulation of DBL-1/BMP by collagen genes. We analyzed four DBL-1-regulated collagen genes that affect body size. Here we show that inactivation of any one of these cuticle collagen genes reduces DBL-1/BMP signaling, as measured by a Smad activity reporter. Furthermore, we find that depletion of these collagens reduces GFP::DBL-1 fluorescence, and acts unexpectedly at the level of dbl-1 transcription. We therefore conclude that cuticle, a type of ECM, impinges on DBL-1/BMP expression and signaling. In contrast to other characterized examples, however, the feedback regulation of DBL-1/BMP signaling by collagens is likely to be contact-independent, due to the physical separation of the cuticle from DBL-1-expressing cells in the ventral nerve cord. Our results provide an entry point into a novel mechanism of regulation of BMP signaling, with broader implications for mechanical regulation of gene expression in general.

scholarly journals Genetic interactions between the DBL-1/BMP-like pathway and dpy body size–associated genes in Caenorhabditis elegans

2019 ◽  
Vol 30 (26) ◽  
pp. 3151-3160 ◽  
Author(s):  
Mohammed Farhan Lakdawala ◽  
Bhoomi Madhu ◽  
Lionel Faure ◽  
Mehul Vora ◽  
Richard W. Padgett ◽  
...  
Keyword(s):  
Body Size ◽  
Caenorhabditis Elegans ◽  
Bmp Signaling ◽  
Genetic Interactions ◽  
Set Domain ◽  
Downstream Targets ◽  
Ecm Proteins ◽  
Domain Protein

How BMP signaling and other body size regulators interact is not clear. We found interactions between Caenorhabditis elegans DBL-1/BMP and ECM, proteins that may modify or secrete DBL-1, and the SET domain protein BLMP-1. DBL-1 signaling may control downstream targets, some through BLMP-1, that affect size either directly or by feeding back on DBL-1 signaling.

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