Loss of Memo, a novel FGFR regulator, results in reduced lifespan

Haenzi, Barbara; Bonny, Olivier; Masson, Régis; Lienhard, Susanne; Dey, Julien H.; Kuro‐o, Makoto; Hynes, Nancy E.

doi:10.1096/fj.13-228320

Cited by 26 publications

(107 citation statements)

References 27 publications

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“…Previous reports have identified a generally ubiquitous expression pattern for Memo1 during embryonic development as well as expression within most adult organs 22,27 . However, a more thorough analysis of Memo1 expression, specifically within the craniofacial region during key stages of development, has not been carried out.…”

Section: Resultsmentioning

confidence: 93%

“…First, MEMO1 may facilitate signaling downstream of an RTK during cranial base ossification. Specifically, analyses in other physiological and developmental processes have shown that MEMO1 mediates signaling downstream of a variety of RTKs, including ERBB2 19,59 , EGFR 19 , FGFR 19,27 , IGF1R 59 , and PDGFR 22 . Interestingly, previous work has also identified a role for these signaling pathways, including their effectors such as ERK1/2, in driving endochondral ossification, either in the cranial base directly or other endochondral bones 60-65 .…”

Section: Discussionmentioning

confidence: 99%

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MEMO1 drives cranial endochondral ossification and palatogenesis

Otterloo

Feng

Jones

et al. 2016

Developmental Biology

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The cranial base is a component of the neurocranium and has a central role in the structural integration of the face, brain and vertebral column. Consequently, alteration in the shape of the human cranial base has been intimately linked with primate evolution and defective development is associated with numerous human facial abnormalities. Here we describe a novel recessive mutant mouse strain that presented with a domed head and fully penetrant cleft secondary palate coupled with defects in the formation of the underlying cranial base. Mapping and non-complementation studies revealed a specific mutation in Memo1 - a gene originally associated with cell migration. Expression analysis of Memo1 identified robust expression in the perichondrium and periosteum of the developing cranial base, but only modest expression in the palatal shelves. Fittingly, although the palatal shelves failed to elevate in Memo1 mutants, expression changes were modest within the shelves themselves. In contrast, the cranial base, which forms via endochondral ossification had major reductions in the expression of genes responsible for bone formation, notably matrix metalloproteinases and markers of the osteoblast lineage, mirrored by an increase in markers of cartilage and extracellular matrix development. Concomitant with these changes, mutant cranial bases showed an increased zone of hypertrophic chondrocytes accompanied by a reduction in both vascular invasion and mineralization. Finally, neural crest cell-specific deletion of Memo1 caused a failure of anterior cranial base ossification indicating a cell autonomous role for MEMO1 in the development of these neural crest cell derived structures. However, palate formation was largely normal in these conditional mutants, suggesting a non-autonomous role for MEMO1 in palatal closure. Overall, these findings assign a new function to MEMO1 in driving endochondral ossification in the cranium, and also link abnormal development of the cranial base with more widespread effects on craniofacial shape relevant to human craniofacial dysmorphology.

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Section: Resultsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

MEMO1 drives cranial endochondral ossification and palatogenesis

Otterloo

Feng

Jones

et al. 2016

Developmental Biology

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“…90 Memo is a newly discovered downstream effector of FGFR signaling. 91 Memo-deficient mice have some characteristics in common with FGF23/Klotho mice (namely, a short life span, low PTH levels and elevated calcitriol and calcium levels) but differ in terms of phosphate levels. In vitro experiments revealed that Memo downregulation only partially inhibits FGFR signaling; this could explain why a lack of Memo in vivo does not result in hyperphosphatemia.…”

Section: Fgf-23/klotho Axismentioning

confidence: 99%

Vascular Toxicity of Phosphate in Chronic Kidney Disease

Gross

Six

Kamel

et al. 2014

Circ J

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In epidemiological studies of CKD patients and the general population, high phosphate levels are associated with CV disease (CVD). The association is even observed in early-stage CKD and is independent of other traditional CV risk factors. 5, 6 Along with other factors, hyperphosphatemia is involved in the development of vascular calcification (VC) and endothelial dysfunction (ED), 7-9 both of which are major nontraditional CV risk factors for CKD. Phosphate is able to act either directly on these parameters or indirectly via the FGF23/Klotho and PTH axes (Figure 1).We review the various effects of hyperphosphatemia on CV parameters, with a focus on its emerging role in ED. The efficacy of current therapies for improving phosphate-related CV outcomes is also discussed. Direct Effects of Phosphate on CV Calcification and ED Epidemiological and Interventional StudiesVC is deposition of calcium/phosphate, mostly as apatite, in the blood vessels, myocardium and cardiac valves. Calcification of both the intima and media occurs in CKD, 10 resulting in the stiffness of the large arteries (as evidenced by a higher pulse wave velocity) and thus promotion of CV morbidity/ mortality. The results of several epidemiological studies have highlighted an association between serum phosphate levels and VC in stage 5D CKD patients, 11,12 in early-stage CKD patients and in the general population (in whom serum phosphate levels are still within the normal range). 13, 14 Indeed, 2 elegant prospective studies of large cohorts of hosphate, principally provided by food, is involved in many physiological processes: it buffers the intracellular pH, ensures the stability of the skeleton and contributes to many essential biological functions (eg, DNA synthesis, cell membrane phospholipids, energy metabolism and intracellular signaling pathways that are regulated by phosphorylation/dephosphorylation).The physiological concentration of phosphate (0.8-1.5 mmol/L) is tightly regulated by, among others, the fibroblast growth factor 23 (FGF23)/Klotho axis, parathyroid hormone (PTH) and calcitriol (the active form of vitamin D). 1 In chronic kidney disease (CKD), the progressive loss of functional nephrons induces retention of phosphate, which in turn leads to (1) an increase in calcium/phosphate products and (2) FGF23 synthesis. With the aim of preventing hyperphosphatemia, FGF23 decreases circulating levels of calcitriol, thus inhibiting intestinal phosphate and calcium absorption. PTH, the overexpression of which is triggered by hypocalcemia, stimulates bone resorption for the primary purpose of restoring calcemia but in doing so it increases phosphatemia and thus the calcium/phosphate products. During the course of CKD, Klotho's downregulation in both the parathyroid gland and the kidney results in the loss of FGF23 being able to respectively (1) decrease PTH expression and (2) inhibit renal phosphate reabsorption. In late-stage CKD, the few remaining functional nephrons are no longer able to eliminate phosphate and a vicious circle (referred ...

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“…Mediator of ErbB2‐driven cell Motility (MEMO) was discovered during a screen for proteins needed for cancer cell migration activated upon ErbB2 receptor phosphorylation . It is encoded by MEMO1 , an evolutionary conserved gene that is ubiquitously expressed in mammalian tissues . Intracellular Memo protein is required for cellular responses to heregulin, epidermal and fibroblast growth factors (EGF, FGF), and estrogen .…”

Section: Introductionmentioning

confidence: 99%

Redox‐Dependent Bone Alkaline Phosphatase Dysfunction Drives Part of the Complex Bone Phenotype in Mice Deficient for Memo1

et al. 2018

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Mediator of ErbB2-driven cell Motility 1 (MEMO1) is an intracellular redox protein that integrates growth factors signaling with the intracellular redox state. We have previously reported that mice lacking Memo1 displayed higher plasma calcium levels and other alterations of mineral metabolism, but the underlying mechanism was unresolved and the bone phenotype was not described. Here, we show that Cre/lox-mediated MEMO1 deletion in the whole body of C57Bl/6 mice (Memo cKO) leads to severely altered trabecular bone and lower mineralization, with preserved osteoblast and osteoclast number and activity, but altered osteoblast response to epidermal growth factor (EGF) and FGF2. More strikingly, Memo cKO mice display decreased alkaline phosphatase (ALP) activity in serum and in bone, while ALPL expression level is unchanged. Bone intracellular redox state is significantly altered in Memo cKO mice and we inferred that ALP dimerization was reduced in Memo cKO mice. Indeed, despite similar ALP oxidation, we found increased ALP sensitivity to detergent in Memo cKO bone leading to lower ALP dimerization capability. Thus, we report a severe bone phenotype and dysfunctional bone ALP with local alteration of the redox state in Memo cKO mice that partially mimics hypophosphatasia, independent of ALPL mutations. These findings reveal Memo as a key player in bone homeostasis and underline a role of bone redox state in controlling ALP activity.

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Loss of Memo, a novel FGFR regulator, results in reduced lifespan

Cited by 26 publications

References 27 publications

MEMO1 drives cranial endochondral ossification and palatogenesis

MEMO1 drives cranial endochondral ossification and palatogenesis

Vascular Toxicity of Phosphate in Chronic Kidney Disease

Redox‐Dependent Bone Alkaline Phosphatase Dysfunction Drives Part of the Complex Bone Phenotype in Mice Deficient for Memo1

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