scholarly journals Apcdd1 is a dual BMP/Wnt inhibitor in the developing nervous system and skin

2019 ◽  
Author(s):  
Alin Vonica ◽  
Neha Bhat ◽  
Keith Phan ◽  
Jinbai Guo ◽  
Lăcrimioara Iancu ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Bmp Signaling ◽  
Protein Domain ◽  
Axis Formation ◽  
Intercellular Signaling ◽  
Functional Protein ◽  
Animal Development ◽  
Bmp Receptors ◽  
Wnt Inhibitor

AbstractAnimal development and homeostasis depend on precise temporal and spatial intercellular signaling. Components shared between signaling pathways, generally thought to decrease specificity, paradoxically can also provide a solution to pathway coordination. Here we show that the Bone Morphogenetic Protein (BMP) and Wnt signaling pathways share Apcdd1 as a common inhibitor and that Apcdd1 is a taxon-restricted gene with novel domains and signaling functions. Previously, we showed that Apcdd1 inhibits Wnt signaling, here we find that Apcdd1 potently inhibits BMP signaling in body axis formation and neural differentiation in chicken, frog, zebrafish, and humans. Our results from experiments and modeling suggest that Apcdd1 may coordinate the outputs of two signaling pathways central to animal development and human disease.Significance StatementApcdd1 is a taxon-restricted gene that inhibits both BMP and Wnt intercellular signaling pathways in multiple organisms including mice, frog, zebrafish, and chicken. It encodes a bi-functional protein with a novel protein domain that can bind to Wnt and BMP receptors and block downstream signaling.

scholarly journals Eukaryotic initiation factor 4A3 inhibits Wnt/β-catenin signaling and regulates axis formation in zebrafish embryos

Development ◽  
2021 ◽  
Author(s):  
Bo Wang ◽  
Xiaozhi Rong ◽  
Yumei Zhou ◽  
Yunzhang Liu ◽  
Jiqin Sun ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Target Genes ◽  
Transcription Activation ◽  
Initiation Factor ◽  
Exon Junction Complex ◽  
Axis Formation ◽  
Zebrafish Embryos ◽  
Eukaryotic Initiation Factor ◽  
Wnt Inhibitor ◽  
Transcriptional Complex

A key step in the activation of canonical Wnt signaling is the interaction between β-catenin and Tcf/Lefs that forms the transcription activation complex and facilitates the expression of target genes. Eukaryotic initiation factor 4A3 (EIF4A3) is an ATP-dependent DEAD box-family RNA helicase and acts as a core subunit of the exon junction complex (EJC) to control a series of RNA posttranscriptional processes. In this study, we uncovered that EIF4A3 functions as a Wnt inhibitor by interfering with the formation of β-catenin/Tcf transcription activation complex. As Wnt stimulation increases, accumulated β-catenin displaces EIF4A3 from a transcriptional complex with Tcf/Lef, allowing the active complex to facilitate the expression of target genes. In zebrafish embryos, eif4a3 depletion inhibited the development of the dorsal organizer and pattern formation of the anterior neuroectoderm by increasing Wnt/β-catenin signaling. Conversely, overexpression of eif4a3 decreased Wnt/β-catenin signaling and inhibited the formation of the dorsal organizer before gastrulation. Our results reveal novel roles of EIF4A3 in the inhibition of Wnt signaling and the regulation of embryonic development in zebrafish.

scholarly journals Early Head Specification in Xenopus laevis

2003 ◽  
Vol 3 ◽  
pp. 655-676
Author(s):  
Blue B. Lake ◽  
Kenneth R. Kao
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Neural Tube ◽  
Intracellular Signaling ◽  
Organizer Region ◽  
Dorsal Side ◽  
Bmp Signaling ◽  
The Body ◽  
Normal Brain ◽  
Sequence Of Events

The head represents the most dorsal and anterior extent of the body axis. InXenopus, the progressive determination of the head is an extremely complex process involving the activation and localized antagonism of a number of interdependent intracellular signaling pathways including the Wingless/Int-1 (Wnt), bone morphogenetic protein (BMP), and nodal-related pathways. The sequence of events that specify the head are: dorsal-ventral polarization and head organizer specification in the blastula; gastrulation; neural induction; and patterning of the anterior-posterior and dorsal-ventral neuraxes. Wnt signaling is required for the specification of the dorsal side initially but is then inhibited within the organizer once it has formed. Similarly, Wnt signaling is required along the length of the neural tube, but must be suppressed at its rostral end for normal brain development. Nodal signaling is also necessary for induction of the mesendoderm, but is subsequently suppressed in its dorsal-anterior extreme to specify head organizer. BMP signaling is required for ventral mesoderm and non-neural ectoderm, and must also be suppressed in the head organizer region and for the differentiation of the ventral midline of the neural tube. Thus, development of the head, and indeed the body plan in general, requires precisely timed and spatially restricted activation and repression of these signaling pathways.

scholarly journals Feedback control of Wnt signaling based on histidine cluster co-aggregation between Naked/NKD and Axin

2020 ◽  
Author(s):  
Melissa Gammons ◽  
Miha Renko ◽  
Joshua E. Flack ◽  
Juliusz Mieszczanek ◽  
Mariann Bienz
Keyword(s):  
Feedback Control ◽  
Epithelial Cells ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Molecular Mechanism ◽  
Tissue Homeostasis ◽  
Animal Development ◽  
Universal Feature ◽  
Feedback Regulator ◽  
Cell Signaling Pathways

ABSTRACTFeedback control is a universal feature of cell signaling pathways. Naked/NKD is a widely conserved feedback regulator of Wnt signaling which controls animal development and tissue homeostasis. Naked/NKD destabilizes Dishevelled, which assembles Wnt signalosomes to inhibit the β-catenin destruction complex via recruitment of Axin. Here, we discover that the molecular mechanism underlying Naked/NKD function relies on its assembly into ultrastable decameric core aggregates via its conserved C-terminal histidine cluster (HisC). HisC aggregation is facilitated by Dishevelled and depends on accumulation of Naked/NKD during prolonged Wnt stimulation. Naked/NKD HisC cores co-aggregate with a conserved histidine cluster within Axin, to destabilize it along with Dishevelled, possibly via the autophagy receptor p62 which binds to HisC aggregates. Consistent with this, attenuated Wnt responses are observed in CRISPR-engineered flies and human epithelial cells whose HisC has been deleted. Thus, HisC aggregation by Naked/NKD provides context-dependent feedback control of prolonged Wnt responses.

scholarly journals Runx1 is a central regulator of osteogenesis for bone homeostasis by orchestrating BMP and WNT signaling pathways

PLoS Genetics ◽  
2021 ◽  
Vol 17 (1) ◽  
pp. e1009233
Author(s):  
Chen-Yi Tang ◽  
Mengrui Wu ◽  
Dongfeng Zhao ◽  
Diep Edwards ◽  
Abigail McVicar ◽  
...  
Keyword(s):  
Bone Loss ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Skeletal Development ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Sequencing Analysis ◽  
Bone Homeostasis ◽  
Promoter Regions

Runx1 is highly expressed in osteoblasts, however, its function in osteogenesis is unclear. We generated mesenchymal progenitor-specific (Runx1f/fTwist2-Cre) and osteoblast-specific (Runx1f/fCol1α1-Cre) conditional knockout (Runx1 CKO) mice. The mutant CKO mice with normal skeletal development displayed a severe osteoporosis phenotype at postnatal and adult stages. Runx1 CKO resulted in decreased osteogenesis and increased adipogenesis. RNA-sequencing analysis, Western blot, and qPCR validation of Runx1 CKO samples showed that Runx1 regulates BMP signaling pathway and Wnt/β-catenin signaling pathway. ChIP assay revealed direct binding of Runx1 to the promoter regions of Bmp7, Alk3, and Atf4, and promoter mapping demonstrated that Runx1 upregulates their promoter activity through the binding regions. Bmp7 overexpression rescued Alk3, Runx2, and Atf4 expression in Runx1-deficient BMSCs. Runx2 expression was decreased while Runx1 was not changed in Alk3 deficient osteoblasts. Atf4 overexpression in Runx1-deficient BMSCs did not rescue expression of Runx1, Bmp7, and Alk3. Smad1/5/8 activity was vitally reduced in Runx1 CKO cells, indicating Runx1 positively regulates the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 signaling pathway. Notably, Runx1 overexpression in Runx2-/- osteoblasts rescued expression of Atf4, OCN, and ALP to compensate Runx2 function. Runx1 CKO mice at various osteoblast differentiation stages reduced Wnt signaling and caused high expression of C/ebpα and Pparγ and largely increased adipogenesis. Co-culture of Runx1-deficient and wild-type cells demonstrated that Runx1 regulates osteoblast−adipocyte lineage commitment both cell-autonomously and non-autonomously. Notably, Runx1 overexpression rescued bone loss in OVX-induced osteoporosis. This study focused on the role of Runx1 in different cell populations with regards to BMP and Wnt signaling pathways and in the interacting network underlying bone homeostasis as well as adipogenesis, and has provided new insight and advancement of knowledge in skeletal development. Collectively, Runx1 maintains adult bone homeostasis from bone loss though up-regulating Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/β-Catenin signaling pathways, and targeting Runx1 potentially leads to novel therapeutics for osteoporosis.

The Bone Morphogenetic Protein (BMP)-4 Is Involved in the Regulation of Human Megakaryocytic Differentiation during Thrombopoietin Signaling.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1339-1339
Author(s):  
Franck E Nicolini ◽  
Sandrine Jeanpierre ◽  
Bastien Kaniewski ◽  
Charles Dumontet ◽  
Ruth Rimokh ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Activin A ◽  
Bmp Signaling ◽  
Receptor Expression ◽  
Autocrine Loop ◽  
Megakaryocytic Differentiation ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
The Impact

Abstract It has been shown in the past that Activin A, BMP-2 and BMP-4, three members of the TGF-β family, are involved in the regulation of hematopoiesis and particularly erythropoiesis, in humans. In this study, we explored the role of these molecules in human megakaryopoiesis using an in vitro serum-free assay initiated with purified normal CD34+ human bone marrow (BM) cells (from allogeneic BM donors), that allows the analysis of the impact of such molecules on all stages of megakaryocytic differentiation. We could demonstrate for the first time, that in the absence of thrombopoietin (TPO), BMP-4 is able to induce CD34+ progenitor commitment and differentiation into megakaryocytes throughout all stages through means of cytology, flow cytometry, CFU and LTC-IC and ploidy assays, as well as in vitro platelet production. We analyzed as well the expression of megakaryocytic specific factors such as FOG-2, Fli-1 and PF4 by RQ-PCR, and PF4, BMP-4 secretion in culture supernatants. While we have previously shown that Activin A and BMP-2 are involved in the erythropoietic commitment even in the absence of erythropoietin, we were not able to demonstrate any effect of these molecules on megakaryopoietic commitment and differentiation. Using signaling pathways specific inhibitors such as AG490 (JAK-2 pathway inhibitor), PD98059 (ERK pathway inhibitor), LY294002 (PI3-K inhibitor) and Rapamycin (mTOR pathway inhibitor), we could show that BMP-4, as TPO, exerts its effects on human megakaryopoiesis involving specifically the JAK/STAT and mTOR signaling pathways. In addition, the specific inhibition of the BMP signaling pathway with blocking antibodies (CD34+ BM cells cultured in the presence of anti-TPO-R and mouse anti-BMP-4 Antibody), natural soluble inhibitors [such as FLRG (Follistatin related gene) protein or Follistatin], or soluble BMP-receptors (sBMPR-Ia, sBMPR-Ib) has revealed that TPO uses the BMP-4 pathway to induce the megakaryopoietic commitment of human BM CD34+ progenitors. Finally, we could demonstrate that TPO up-regulates a BMP-4 autocrine loop in megakaryocytic progenitors, by inducing their own production of BMP-4 associated to an up-regulation of BMP-receptor expression. In conclusion, this study illustrates that BMP-4 represents an important actor in the regulation of human megakaryopoiesis.

scholarly journals Crosstalk of Intercellular Signaling Pathways in the Generation of Midbrain Dopaminergic Neurons In Vivo and from Stem Cells

2019 ◽  
Vol 7 (1) ◽  
pp. 3 ◽  
Author(s):  
Claude Brodski ◽  
Sandra Blaess ◽  
Juha Partanen ◽  
Nilima Prakash
Keyword(s):  
Stem Cell ◽  
Signaling Pathways ◽  
Current Knowledge ◽  
Integration Site ◽  
Bmp Signaling ◽  
Intercellular Signaling ◽  
Mammalian Embryo ◽  
Fibroblast Growth Factor 8

Dopamine-synthesizing neurons located in the mammalian ventral midbrain are at the center stage of biomedical research due to their involvement in severe human neuropsychiatric and neurodegenerative disorders, most prominently Parkinson’s Disease (PD). The induction of midbrain dopaminergic (mDA) neurons depends on two important signaling centers of the mammalian embryo: the ventral midline or floor plate (FP) of the neural tube, and the isthmic organizer (IsO) at the mid-/hindbrain boundary (MHB). Cells located within and close to the FP secrete sonic hedgehog (SHH), and members of the wingless-type MMTV integration site family (WNT1/5A), as well as bone morphogenetic protein (BMP) family. The IsO cells secrete WNT1 and the fibroblast growth factor 8 (FGF8). Accordingly, the FGF8, SHH, WNT, and BMP signaling pathways play crucial roles during the development of the mDA neurons in the mammalian embryo. Moreover, these morphogens are essential for the generation of stem cell-derived mDA neurons, which are critical for the modeling, drug screening, and cell replacement therapy of PD. This review summarizes our current knowledge about the functions and crosstalk of these signaling pathways in mammalian mDA neuron development in vivo and their applications in stem cell-based paradigms for the efficient derivation of these neurons in vitro.

scholarly journals R-spondins are BMP receptor antagonists in Xenopus early embryonic development

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hyeyoon Lee ◽  
Carina Seidl ◽  
Rui Sun ◽  
Andrey Glinka ◽  
Christof Niehrs
Keyword(s):  
Bmp Signaling ◽  
Axis Formation ◽  
Type I ◽  
Bmp Receptor ◽  
Affinity Ligand ◽  
Physiological Processes ◽  
Bmp Receptors ◽  
Bifunctional Ligands ◽  
Feedback Inhibitor ◽  
And Function

Abstract BMP signaling plays key roles in development, stem cells, adult tissue homeostasis, and disease. How BMP receptors are extracellularly modulated and in which physiological context, is therefore of prime importance. R-spondins (RSPOs) are a small family of secreted proteins that co-activate WNT signaling and function as potent stem cell effectors and oncogenes. Evidence is mounting that RSPOs act WNT-independently but how and in which physiological processes remains enigmatic. Here we show that RSPO2 and RSPO3 also act as BMP antagonists. RSPO2 is a high affinity ligand for the type I BMP receptor BMPR1A/ALK3, and it engages ZNRF3 to trigger internalization and degradation of BMPR1A. In early Xenopus embryos, Rspo2 is a negative feedback inhibitor in the BMP4 synexpression group and regulates dorsoventral axis formation. We conclude that R-spondins are bifunctional ligands, which activate WNT- and inhibit BMP signaling via ZNRF3, with implications for development and cancer.

scholarly journals The interaction of Notch and Wnt signaling pathways in vertebrate regeneration

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Junying Gao ◽  
Lixia Fan ◽  
Long Zhao ◽  
Ying Su
Keyword(s):  
Wnt Signaling ◽  
Notch Signaling ◽  
Signaling Pathways ◽  
Mammalian Species ◽  
Therapeutic Strategies ◽  
Animal Development ◽  
Spatiotemporal Regulation ◽  
Organ Regeneration ◽  
Evolutionarily Conserved ◽  
Molecular Bases

AbstractRegeneration is an evolutionarily conserved process in animal kingdoms, however, the regenerative capacities differ from species and organ/tissues. Mammals possess very limited regenerative potential to replace damaged organs, whereas non-mammalian species usually have impressive abilities to regenerate organs. The regeneration process requires proper spatiotemporal regulation from key signaling pathways. The canonical Notch and Wnt signaling pathways, two fundamental signals guiding animal development, have been demonstrated to play significant roles in the regeneration of vertebrates. In recent years, increasing evidence has implicated the cross-talking between Notch and Wnt signals during organ regeneration. In this review, we summarize the roles of Notch signaling and Wnt signaling during several representative organ regenerative events, emphasizing the functions and molecular bases of their interplay in these processes, shedding light on utilizing these two signaling pathways to enhance regeneration in mammals and design legitimate therapeutic strategies.

scholarly journals Feedback control of Wnt signaling based on ultrastable histidine cluster co-aggregation between Naked/NKD and Axin

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Melissa V Gammons ◽  
Miha Renko ◽  
Joshua E Flack ◽  
Juliusz Mieszczanek ◽  
Mariann Bienz
Keyword(s):  
Feedback Control ◽  
Epithelial Cells ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Molecular Mechanism ◽  
Tissue Homeostasis ◽  
Animal Development ◽  
Universal Feature ◽  
Feedback Regulator ◽  
Cell Signaling Pathways

Feedback control is a universal feature of cell signaling pathways. Naked/NKD is a widely conserved feedback regulator of Wnt signaling which controls animal development and tissue homeostasis. Naked/NKD destabilizes Dishevelled, which assembles Wnt signalosomes to inhibit the β-catenin destruction complex via recruitment of Axin. Here, we discover that the molecular mechanism underlying Naked/NKD function relies on its assembly into ultra-stable decameric core aggregates via its conserved C-terminal histidine cluster (HisC). HisC aggregation is facilitated by Dishevelled and depends on accumulation of Naked/NKD during prolonged Wnt stimulation. Naked/NKD HisC cores co-aggregate with a conserved histidine cluster within Axin, to destabilize it along with Dishevelled, possibly via the autophagy receptor p62, which binds to HisC aggregates. Consistent with this, attenuated Wnt responses are observed in CRISPR-engineered flies and human epithelial cells whose Naked/NKD HisC has been deleted. Thus, HisC aggregation by Naked/NKD provides context-dependent feedback control of prolonged Wnt responses.

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