A critical role for sFRP proteins in maintaining caudal neural tube closure in mice via inhibition of BMP signaling

Misra, Kamana; Matise, Michael P.

doi:10.1016/j.ydbio.2009.10.015

Cited by 41 publications

(37 citation statements)

References 56 publications

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“…Despite restricted mRNA expression, Sfrp proteins efficiently diffuse in the extracellular space 17 and Sfrp1 was immunodetected, albeit at low levels, also in the neural retina (Fig. S1), supporting the proposed Sfrp functional redundancy 9,11,12 .…”

Section: Sfrp1 and Sfrp2 Are Essential For Proper Eye Developmentsupporting

confidence: 62%

“…First, Sfrp function might be redundant, because genetic inactivation of individual family members in mice seems to have little effect on embryonic development 9,10 . Double inactivation of Sfrp1 and Sfrp2 causes instead a variety of alterations 9,11,12 , some of which are worsened by the additional inactivation of Sfrp5 9,11 . Second, Sfrps have Wnt-independent functions 9,12 because Sfrp null phenotypes are only partially explained by overactivation of Wnt/βcatenin signaling 11 or alterations in the non-canonical Wnt/PCP pathway.…”

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confidence: 99%

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SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

et al. 2011

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It is well established that embryonic mouse retinal neurogenesis requiresNotch and Wnt signaling are also required for the development of vertebrate neural retina.This structure develops from a neuroepithelium composed of multipotent progenitors, which undergo a series of competence states to give rise to six neuronal and one glial cell types 2 . As progenitor cells produce the various cell types, Notch through lateral inhibition, maintains neighboring cells in a multipotent, proliferative state, ensuring that sufficient numbers of progenitors are retained for consecutive waves of neurogenesis. Thus, downregulation of Notch is a prerequisite for retinal neuronal differentiation 2 .Wnt/βcatenin signaling has also been implicated in the proliferation of vertebrate retinal precursors. However, in the mouse embryonic neural retina this function is limited to progenitor cells located in the periphery 3, 4 . In contrast, Wnt/βcatenin signaling is not active in the central retina and cell proliferation and differentiation proceed normally in mice with conditional deletion of βcatenin in the neural retina, although retinal lamination is altered 5 .Similarly, retinal specific inactivation of Fzd5, a non-canonical Wnt receptor mostly impacts on retinal vasculature formation but has no effect on neurogenesis 6 By analyzing the functional consequences of Sfrp1 and Sfrp2 compound inactivation during mouse retinal neurogenesis, we demonstrate here a novel and Wnt-independent role of Sfrps in the regulation of Notch signaling. We explain this finding by demonstrating that Sfrps can bind and downregulate the activity of ADAM10, a metalloprotease with multiple substrates including Notch, N-cadherin and APP. 4 RESULTS Sfrp1 and Sfrp2 are essential for proper eye developmentSfrp1 and Sfrp2 are expressed during murine eye development with a complementary pattern that includes all eye structures 7 . Sfrp1 transcripts are localized to the optic cup periphery and the retina pigmented epithelium from E10.5, while Sfrp2 is predominant in the neural retina (Fig. S1). Despite restricted mRNA expression, Sfrp proteins efficiently diffuse in the extracellular space 17 and Sfrp1 was immunodetected, albeit at low levels, also in the neural retina (Fig. S1), supporting the proposed Sfrp functional redundancy 9, 11, 12 .Accordingly, the eye of Sfrp1 and Sfrp2 single null embryos appeared histologically normal.In contrast at E16.5, the latest viable stage, the eyes of Sfrp1 -/-;Sfrp2 -/-compound mutants (n=20) were smaller than those of control littermates (n=30) with morphological visible alterations, including dorsal peripheral defects, reduction of the lens size, abnormal cornea and eye lid formation, increased thickness of the neural retina and abnormal vitreal accumulation of mesenchyme-derived angioblasts that normally form the hyaloid artery, the major vascular structure of the embryonic eye (Fig. S2). Inactivation of Sfrp1/2 alters retinal neurogenesisMultipotent progenitors in the neural retina generates neuronal and one glial cells wi...

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Section: Sfrp1 and Sfrp2 Are Essential For Proper Eye Developmentsupporting

confidence: 62%

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confidence: 99%

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

et al. 2011

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“…In a cell-free in vitro system, mouse sFRP2 interacted with Xenopus Xlr to prevent the degradation of Xenopus chordin (34). Another recent report suggests sFRP2 may play a role in BMP inhibition in the developing embryo; unilateral electroporation of murine BMP and sFRP2 into the chick neural tube blocked the induction of BMP downstream targets (35). This study did not address whether the observed BMP inhibition was an indirect or a direct effect of sFRP2.…”

Section: Discussionmentioning

confidence: 88%

sFRP2 Suppression of Bone Morphogenic Protein (BMP) and Wnt Signaling Mediates Mesenchymal Stem Cell (MSC) Self-renewal Promoting Engraftment and Myocardial Repair

Alfaro

Vincent

Saraswati

et al. 2010

Journal of Biological Chemistry

106

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Transplantation of mesenchymal stem cells (MSCs) is a promising therapy for ischemic injury; however, inadequate survival of implanted cells in host tissue is a substantial impediment in the progress of cellular therapy. Secreted Frizzled-related protein 2 (sFRP2) has recently been highlighted as a key mediator of MSC-driven myocardial and wound repair. Notably, sFRP2 mediates significant enhancement of MSC engraftment in vivo. We hypothesized that sFRP2 improves MSC engraftment by modulating self-renewal through increasing stem cell survival and by inhibiting differentiation. In previous studies we demonstrated that sFRP2-expressing MSCs exhibited an increased proliferation rate. In the current study, we show that sFRP2 also decreased MSC apoptosis and inhibited both osteogenic and chondrogenic lineage commitment. sFRP2 activity occurred through the inhibition of both Wnt and bone morphogenic protein (BMP) signaling pathways. sFRP2-mediated inhibition of BMP signaling, as assessed by levels of pSMAD 1/5/8, was independent of its effects on the Wnt pathway. We further hypothesized that sFRP2 inhibition of MSC lineage commitment may reduce heterotopic osteogenic differentiation within the injured myocardium, a reported adverse side effect. Indeed, we found that sFRP2-MSC-treated hearts and wound tissue had less ectopic calcification. This work provides important new insight into the mechanisms by which sFRP2 increases MSC self-renewal leading to superior tissue engraftment and enhanced wound healing.Bone marrow-derived mesenchymal stem cells (MSCs) 2 are an attractive candidate for cell-mediated wound repair. Because of their plasticity, MSCs have been utilized in several preclinical and clinical trials of tissue regeneration (1).3 MSCs have been able to repair infarcted myocardium, bone, and soft tissue, albeit with varying degrees of success (3). These promising results are inconsistent, partly due to the low levels of engraftment of MSCs within the injured tissues (4). Hence, strategies to increase survival and engraftment within the wound may enhance MSC therapy.Self-renewal is an intrinsic property of stem cells that allows them to give rise to non-differentiated daughter cells by proliferating, preventing apoptosis, and avoid lineage commitment (5, 6). This process is important for the maintenance of a stem cell pool that, in the case of MSCs, can exert a more robust effect within the context of a wound. Although several cytokines, growth factors, adhesion molecules, and extracellular matrix components have been identified as cues that signal MSCs to differentiate, the molecular signals that modulate MSC self-renewal remain unknown (5). Data from the hematopoietic stem cell (HSC) field have documented the involvement of Wnt, Notch, and BMP signaling cascades in self-renewal; these pathways are implicated in the expansion of undifferentiated HSCs that upon transplantation into lethally irradiated mice successfully reconstitute the cleared bone marrow (7-9). Although no data are available to demonstrate the...

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“…Sfrp-2 is also known to decrease bone formation via regulation of BMP (54). This is likely due to the inhibitory effect of Sfrp-2 on BMP-1 and other tolloid proteases necessary for cleavage and inactivation of BMP antagonists, includ-ing chordin and noggin (10,23,33,36,50), described during developmental processes. Multiple tolloid and proteases can cleave and inactivate secreted BMP antagonists.…”

Section: Discussionmentioning

confidence: 99%

Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

West

Austin

Gaskill

et al. 2014

American Journal of Physiology-Cell Physiology

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May 28, 2014; doi:10.1152/ajpcell.00057.2014.-Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH. pulmonary arterial hypertension; gene array; induced pluripotent stem cell; mesenchymal stromal cell; endothelial cell; heritable pulmonary arterial hypertension; idiopathic pulmonary arterial hypertension; Wnt signaling PULMONARY ARTERIAL HYPERTENSION (PAH) is characterized by vascular remodeling, including endothelial cell (EC) dysfunction and occlusion or rarefaction of the peripheral pulmonary microvasculature. More recently, the contribution of multipotent mesenchymal stromal cells (MSC) to muscularization of microvessels has been described (13). The interactions between the lung microenvironment, vascular EC, and MSC during remodeling in PAH remain unclear. All forms of PAH have a high mortality rate, despite current therapeutic options.Deregulated bone morphogenetic protein (BMP) receptor type II (BMPR2) signaling is strongly associated with the development of PAH in both heritable (BMPR2 mut and Cav1 mut ) and idiopathic cases, although the molecular mechanisms through which BMPR2 derangement promotes PAH are unknown. Unfortunately, most rodent models of PAH do not precisely recapitulate the disease pathology; these models display less substantial pulmonary vascular remodeling in both proximal arteries and distal microvasculature, significantly slowing drug discovery efforts. Current in vitro models overexpressing mutant BMPR2 in cell types of interest are complicated by persistent retention of wild-type (WT) signaling. Moreover, human PAH tissue is limited in quantity, and specimens are typically obtained posttransplant or at autopsy, which limits conclusions about disease initiation and propagation. Previous global gene expression analyses using patient samples to identify risk factors for PAH have ...

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A critical role for sFRP proteins in maintaining caudal neural tube closure in mice via inhibition of BMP signaling

Cited by 41 publications

References 56 publications

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

sFRP2 Suppression of Bone Morphogenic Protein (BMP) and Wnt Signaling Mediates Mesenchymal Stem Cell (MSC) Self-renewal Promoting Engraftment and Myocardial Repair

Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

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