BMP-Smad 1/5/8 signalling in the development of the nervous system

Hegarty, Shane V.; O’Keeffe, Gerard W.; Sullivan, Aideen M.

doi:10.1016/j.pneurobio.2013.07.002

Cited by 136 publications

(132 citation statements)

References 178 publications

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“…In the rat, the axons of the DA neurons in the VM extend towards the forebrain via the medial forebrain bundle from E13, and progressively innervate the striatum shortly thereafter, reaching the dorsal striatum around E20 (Gates et al 2004;Nakamura et al 2000;Specht et al 1981a, b;Verney 1999;Voorn et al 1988). In the first three post-natal weeks, striatal innervation becomes more extensive, while naturally occurring cell death refines these connections (Jackson- Lewis et al 2000;Oo and Burke 1997;Burke 2003;Hegarty et al 2013a; Van den Heuvel and Pasterkamp 2008). This study found that BMPRII and BMPRIb were expressed at steady levels in the VM throughout embryonic development (from E14) and into adulthood (until at least P90), with strong expression levels being detected on DA neurons in the P56 SNpc.…”

Section: Discussionmentioning

confidence: 60%

“…While much progress has been made in understanding the signals that control DA neuron development, less is known about the molecules that promote the growth of DA neurites, which is crucial for the functional integration of transplanted cells into the host parenchyma. However, some molecules, such as Ephs and netrin1, have been identified as regulators of nigrostriatal pathway development in recent years (Hegarty et al 2013a; Van den Heuvel and Pasterkamp 2008). In an attempt to identify new candidate molecules and signalling pathways that may be involved in nigrostriatal development, this study focused on two BMPs, GDF5 and BMP2, since both of these factors have been implicated in axonal growth in (Parikh et al 2011;Hazen et al 2011Hazen et al , 2012Phan et al 2010;Niere et al 2006;Lein et al 1995;Hegarty et al 2013a) and have been shown to have neurotrophic effects on VM DA neurons, specifically survivaland neurite growth-promoting effects (O'Keeffe et al 2004a;Reiriz et al 1999;Jordan et al 1997;Sullivan et al 1997;Hegarty et al 2014).…”

Section: Discussionmentioning

confidence: 99%

“…BMPs are regulators of axonal growth in a number of neuronal populations, with this role best characterised in the dorsal spinal cord (SC) (Parikh et al 2011;Hazen et al 2012;Lein et al 1995;Hegarty et al 2013a;Gratacos et al 2002). The two members of the BMP family of proteins, BMP2 and a related molecule GDF5, have been shown to regulate neurite growth in the dorsal SC (Parikh et al 2011;Hazen et al 2011Hazen et al , 2012Phan et al 2010;Niere et al 2006).…”

Section: Introductionmentioning

confidence: 99%

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Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

et al. 2014

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Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson's disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown. The bone morphogenetic protein (BMP) family regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development. Two related members of this family, BMP2 and growth differentiation factor (GDF)5, have neurotrophic effects, including promotion of neurite growth, on cultured VM DA neurons. However, the molecular mechanisms regulating their effects on DA neurons are unknown. By characterising the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum, this study identified BMP2 and GDF5 as potential regulators of nigrostriatal pathway development. Furthermore, through the use of noggin, dorsomorphin and BMPR/Smad plasmids, this study demonstrated that GDF5-and BMP2-induced neurite outgrowth from cultured VM DA neurons is dependent on BMP type I receptor activation of the Smad 1/5/8 signalling pathway.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

et al. 2014

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“…[14][15][16] Smad1/5/9 signaling actively instructs the development and differentiation of distinct neural lineages from human pluripotent stem cells and neural stem cells at the border between the epidermis and the neural plate. 15,17 In addition, differentiation into a neural lineage can be induced by the IL-6 family of cytokines [e.g., leukemia inhibitory factor (LIF) and ciliary neurotrophic factor and bone morphogenic protein (BMP) family cytokines (e.g., BMP2 and BMP4)], which activate distinct downstream transcription factors such as STAT3 and Smad1. 14,16,18,19 The receptor kinases, such as TGF-b and BMP, activate Smad1 and STAT3 signaling by phosphorylation as phosphorylation plays a central role in their transcriptional activation bridged by p300.…”

Section: Introductionmentioning

confidence: 99%

Multipotent neurogenic fate of mesenchymal stem cell is determined by Cdk4-mediated hypophosphorylation of Smad-STAT3

et al. 2016

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Cyclin-dependent kinase (Cdk) in complex with a corresponding cyclin plays a pivotal role in neurogenic differentiation. In particular, Cdk4 activity acts as a signaling switch to direct human mesenchymal stem cells (MSCs) to neural transdifferentiation. However, the molecular evidence of how Cdk4 activity converts MSCs to neurogenic lineage remains unknown. Here, we found that Cdk4 inhibition in human MSCs enriches the populations of neural stem and progenitor pools rather than differentiated glial and neuronal cell pools. Interestingly, Cdk4 inhibition directly inactivates Smads and subsequently STAT3 signaling by hypophosphorylation, and both Cdk4 and Smads levels are linked during the processes of neural transdifferentiation and differentiation. In summary, our results provide novel molecular evidence in which Cdk4 inhibition leads to directing human MSCs to a multipotent neurogenic fate by inactivating Smads-STAT3 signaling.

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“…Moreover, the therapeutic index of gene inhibitors against some of these transcription factors may be limited given their homeostatic role in tissues other than cartilage, for example, HIF-2α is required for maintenance of cardiorespiratory homeostasis and carotid body function and SMAD1/5/8 are key regulators of neural development. 13,14 However, these limitations could potentially be offset through local IA use of chondrocytetargeted nanoparticles, which could boost the accumulation of drugs inside chondrocytes and abate off-targeting effects. Pi et al 6 were able to boost the accumulation of anti-Hif-2α siRNA inside chondrocytes using PEI nanoparticles coated with targeting agents against receptors expressed on anabolic chondrocytes.…”

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confidence: 99%

Tackling chondrocyte hypertrophy with multifunctional nanoparticles

et al. 2016

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Osteoarthritis (OA) is the most common form of arthritis and leads to irreversible changes in all articular tissues and associated skeletal muscle.1,2 OA is a collection of different phenotypic subtypes involving different relative contributions of the stressors and pathogenic pathways that trigger and drive, respectively, disease development ( Figure 1). Recent investigations have shown that OA is driven by interplay between local joint inflammation (synovitis) and chondrocyte impaired bioenergy and protein homeostasis (see Liu-Bryan and Terkeltaub 2 for an excellent review). Another important pathway being studied in the OA field is that chondrocytes acquire a phenotype similar to terminal differentiating chondrocytes found at the growth plate and express markers of hypertrophic chondrocytes including type X collagen, matrix metalloproteinase-13 (MMP13) and vascular endothelial growth factor (VEGF).3 These findings suggest that the loss of phenotypic stability of chondrocytes in OA reflects an early futile process to repair stressed cartilage that ultimately leads to pathologic cartilage calcification.Chondrocyte hypertrophy is regulated by the activation of a constellation of transcription factors and other signalling molecules. Studies with knockout and transgenic mice have shown that deletion of many of these regulators results in resistance to OA development, thus suggesting that blocking chondrocyte hypertrophy by targeting these regulators in chondrocytes would be a valid therapeutic approach for OA. The direct exposure of the cartilage to the joint cavity makes chondrocytes amenable to targeting via intra-articular (IA) injection. This route offers the advantages of high joint bioavailability while reducing the risk of off-target effects. Nevertheless, the delivery of IA-injected small molecules and macromolecules into chondrocytes has been limited by the fast clearance out of the synovial cavity and poor diffusion through the tight cartilage matrix. 4 This problem has been recently tackled through the use of a new class of drugs based upon multifunctional nanoparticles designed to selectively and safely deliver therapeutic agents to a diseased site. 5 In an OA prevention study published in a recent issue of Gene Therapy, Pi et al.6 described the use of polyetheleneimine (PEI) to fabricate chondrocyte-targeting nanoparticles. PEI was first conjugated to a chondrocyte-affinity peptide (CAP; DWRVIIPPRPSAC) and, next, used to condense an siRNA against hypoxia-inducible factor-2α (Hif-2α) in nanoparticles. The nanoparticles were injected weekly into the knees of 8-week-old male Chinese Kun Ming mice at the onset of OA, that is, 3 days after surgical destabilization of the knee joints by dissecting the anterior cruciate ligament (ACL), medial collateral ligament (MCL) and anterior horn of the medial meniscus. After seven weeks, mice treated with CAP-coated nanoparticles showed a significant reduction in cartilage breakdown and synovitis compared with sham-treated mice or OA mice treated with nanoparticles co...

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BMP-Smad 1/5/8 signalling in the development of the nervous system

Cited by 136 publications

References 178 publications

Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

Multipotent neurogenic fate of mesenchymal stem cell is determined by Cdk4-mediated hypophosphorylation of Smad-STAT3

Tackling chondrocyte hypertrophy with multifunctional nanoparticles

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