The mouse osteopetrotic grey-lethal mutation induces a defect in osteoclast maturation/function

Rajapurohitam, Venkatesh; Chalhoub, Nader; Benachenhou, Nadia; Neff, Lynn; Baron, Roland; Vacher, Jean

doi:10.1016/s8756-3282(01)00416-1

Cited by 49 publications

(53 citation statements)

References 33 publications

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“…Normally, the secretory lysosomes produced in osteoclasts (48)(49)(50) participate in the formation of a specific membrane structure, the ruffled border, and regulate secretion of specific proton pumps and enzymes essential for bone matrix degradation (51,52). In Ostm1-null osteoclasts, the lack of Ostm1 vesicles linked to KIF5B cargos would elucidate the virtual absence of ruffled border, resulting in nonfunctional secretory cells, inefficient bone resorption, and osteopetrosis (9). Similarly, defective secretory lysosome and/or organelle dispersion due to loss of Ostm1 is likely the cellular mechanism causing the altered gl/gl immune cell response and hair pigmentation by melanosome clumping (8,10,11).…”

Section: Discussionmentioning

confidence: 99%

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Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking

Pandruvada

Beauregard

Benjannet

et al. 2016

Molecular and Cellular Biology

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In humans and in mice, mutations in the Ostm1 gene cause the most severe form of osteopetrosis, a major bone disease, and neuronal degeneration, both of which are associated with early death. To gain insight into Ostm1 function, we first investigated by sequence and biochemical analysis an immature 34-kDa type I transmembrane Ostm1 protein with a unique cytosolic tail. Mature Ostm1 is posttranslationally processed and highly N-glycosylated and has an apparent mass of ϳ60 kDa. Analysis the subcellular localization of Ostm1 showed that it is within the endoplasmic reticulum, trans-Golgi network, and endosomes/lysosomes. By a wide protein screen under physiologic conditions, several novel cytosolic Ostm1 partners were identified and validated, for which a direct interaction with the kinesin 5B heavy chains was demonstrated. These results determined that Ostm1 is part of a cytosolic scaffolding multiprotein complex, imparting an adaptor function to Ostm1. Moreover, we uncovered a role for the Ostm1/KIF5B complex in intracellular trafficking and dispersion of cargos from the endoplasmic reticulum to late endosomal/lysosomal subcellular compartments. These Ostm1 molecular and cellular functions could elucidate all of the pathophysiologic mechanisms underlying the wide phenotypic spectrum of Ostm1-deficient mice.

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Section: Discussionmentioning

confidence: 99%

“…In gl/gl mice, osteoclast maturation is impaired with defective ruffled border formation, resulting in ineffective bone resorption and mortality at ϳ3 weeks of age (9). Functional rescue of Ostm1 skeletal phenotypes in transgenic mice was obtained by targeting multiple hematopoietic lineages that resulted in osteoclast activation (10).…”

mentioning

confidence: 99%

Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking

Pandruvada

Beauregard

Benjannet

et al. 2016

Molecular and Cellular Biology

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“…FITC signals were visualized by confocal microscopy. Osteoclast activity was detected by staining for tartrate-resistant acid phosphatase (TRAP) using the Sigma Acid Phosphatase, Leukocyte Kit (Rajapurohitam et al, 1997).…”

Section: Histology and Immunostainingmentioning

confidence: 99%

Msx2andTwistcooperatively control the development of the neural crest-derived skeletogenic mesenchyme of the murine skull vault

et al. 2003

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The flat bones of the vertebrate skull vault develop from two migratory mesenchymal cell populations, the cranial neural crest and paraxial mesoderm. At the onset of skull vault development, these mesenchymal cells emigrate from their sites of origin to positions between the ectoderm and the developing cerebral hemispheres. There they combine, proliferate and differentiate along an osteogenic pathway. Anomalies in skull vault development are relatively common in humans. One such anomaly is familial calvarial foramina, persistent unossified areas within the skull vault. Mutations in MSX2 and TWIST are known to cause calvarial foramina in humans. Little is known of the cellular and developmental processes underlying this defect. Neither is it known whether MSX2 and TWIST function in the same or distinct pathways. We trace the origin of the calvarial foramen defect in Msx2 mutant mice to a group of skeletogenic mesenchyme cells that compose the frontal bone rudiment. We show that this cell population is reduced not because of apoptosis or deficient migration of neural crest-derived precursor cells, but because of defects in its differentiation and proliferation. We demonstrate, in addition, that heterozygous loss of Twist function causes a foramen in the skull vault similar to that caused by loss of Msx2 function. Both the quantity and proliferation of the frontal bone skeletogenic mesenchyme are reduced in Msx2-Twist double mutants compared with individual mutants. Thus Msx2 and Twist cooperate in the control of the differentiation and proliferation of skeletogenic mesenchyme. Molecular epistasis analysis suggests that Msx2 and Twist do not act in tandem to control osteoblast differentiation, but function at the same epistatic level.

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“…These gl/gl mice die within 3 weeks of age with defects in the osteoclast hematopoietic lineage (8,10). The murine Ostm1 gene is expressed in several tissues at variable levels.…”

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confidence: 99%

Severe Neurodegeneration with Impaired Autophagy Mechanism Triggered by Ostm1 Deficiency

Héraud

Griffiths

Pandruvada

et al. 2014

Journal of Biological Chemistry

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Background: Although loss of the Ostm1 gene leads to the most severe form of osteopetrosis, Ostm1 is expressed in other tissues, including the CNS. Results: Independently of hematopoietic lineages, loss of Ostm1 results in acute neurodegeneration with enhanced autophagy. Conclusion: We present evidence for an Ostm1 cell-autonomous role in neurons. Significance: This study shows a novel molecular pathogenic mechanism for neurodegeneration-related diseases.

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The mouse osteopetrotic grey-lethal mutation induces a defect in osteoclast maturation/function

Cited by 49 publications

References 33 publications

Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking

Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking

Msx2andTwistcooperatively control the development of the neural crest-derived skeletogenic mesenchyme of the murine skull vault

Severe Neurodegeneration with Impaired Autophagy Mechanism Triggered by Ostm1 Deficiency

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