The Cloning and Developmental Expression of Unconventional Myosin IXA (MYO9A) a Gene in the Bardet–Biedl Syndrome (BBS4) Region at Chromosome 15q22–q23

Gorman, Susan W.; Haider, Neena B.; Grieshammer, Uta; Swiderski, Ruth E.; Kim, Esther; Welch, Juliet W.; Searby, Charles; Leng, Song; Carmi, Rivka; Sheffield, Val C.; Duhl, David M.

doi:10.1006/geno.1999.5867

Cited by 49 publications

(29 citation statements)

References 41 publications

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“…Glycogen branching enzyme deficiency is causative of GSD4 that is characterized by the accumulation of polyglucosan in almost all tissues. Clinical features of the typical GSD4 are failure to thrive, analysis detected mouse Myo9a expression in limb buds, and in situ hybridization to limb buds suggested that Myo9a may be localized to the precartilagenous mesenchyme (65). Also in the same study, Myo9a was shown to be expressed in the skeletal and the nervous systems, 2 important systems where dysfunction may play a role in the formation of arthrogryposis and consistent with the hypothesis that mutations of MYO9A may cause arthrogryposis.…”

Section: L I N I C a L M E D I C I N Esupporting

confidence: 72%

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Bayram

Karaca

Akdemir

et al. 2016

Journal of Clinical Investigation

111

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Section: L I N I C a L M E D I C I N Esupporting

confidence: 72%

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Bayram

Karaca

Akdemir

et al. 2016

Journal of Clinical Investigation

111

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“…1A). Myo9a is predominantly found in the brain (13,23,24) and accordingly we used mouse brain as a positive control in our Western blot analysis (Fig. 1A).…”

Section: Generation Of Myo9b-deficient Mice and Myo9bmentioning

confidence: 99%

Motorized RhoGAP myosin IXb (Myo9b) controls cell shape and motility

Hanley¹,

Kronlage³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

111

138

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Directional motility is a fundamental function of immune cells, which are recruited to sites of pathogen invasion or tissue damage by chemoattractant signals. To move, cells need to generate lamellipodial membrane protrusions at the front and retract the trailing end. These elementary events are initiated by Rho-family GTPases, which cycle between active GTP-bound and inactive GDP-bound states. How the activity of these “molecular switches” is spatially coordinated is only beginning to be understood. Here, we show that myosin IXb (Myo9b), a Rho GTPase-activating protein (RhoGAP) expressed in immune cells, is essential for coordinating the activity of Rho. We generated Myo9b-deficient mice and show that Myo9b −/− macrophages have strikingly defective spreading and polarization. Furthermore, Myo9b −/− macrophages fail to generate lamellipodia in response to a chemoattractant, and migration in a chemotactic gradient is severely impaired. Inhibition of Rho rescues the Myo9b −/− phenotype, but impairs tail retraction. We also found that Myo9b is important in vivo. Chemoattractant-induced monocyte recruitment to the peritoneal cavity is substantially reduced in Myo9b −/− mice. Thus, we identify the “motorized Rho inhibitor” Myo9b as a key molecular component required for spatially coordinated cell shape changes and motility.

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“…The class IX of myosin molecules includes in mammals two members, Myo9a (myr 7) and Myo9b (myr 5), that are both expressed in a number of differentially spliced variants (Bähler, 2008). The Myo9a protein, previously also called myr 7, is expressed during development and in many adult tissues, most abundantly in brain and testis (Chieregatti et al, 1998;Gorman et al, 1999). Class IX myosins comprise in addition to their myosin head domain a tail region that encompasses a C1 domain and a Rho GTPaseactivating protein (RhoGAP) domain (Reinhard et al, 1995;Chieregatti et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Myosin IXa Regulates Epithelial Differentiation and Its Deficiency Results in Hydrocephalus

Abouhamed

Grobe

San

et al. 2009

MBoC

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The ependymal multiciliated epithelium in the brain restricts the cerebrospinal fluid to the cerebral ventricles and regulates its flow. We report here that mice deficient for myosin IXa (Myo9a), an actin-dependent motor molecule with a Rho GTPase-activating (GAP) domain, develop severe hydrocephalus with stenosis and closure of the ventral caudal 3rd ventricle and the aqueduct. Myo9a is expressed in maturing ependymal epithelial cells, and its absence leads to impaired maturation of ependymal cells. The Myo9a deficiency further resulted in a distorted ependyma due to irregular epithelial cell morphology and altered organization of intercellular junctions. Ependymal cells occasionally delaminated, forming multilayered structures that bridged the CSF-filled ventricular space. Hydrocephalus formation could be significantly attenuated by the inhibition of the Rho-effector Rho-kinase (ROCK). Administration of ROCK-inhibitor restored maturation of ependymal cells, but not the morphological distortions of the ependyma. Similarly, down-regulation of Myo9a by siRNA in Caco-2 adenocarcinoma cells increased Rho-signaling and induced alterations in differentiation, cell morphology, junction assembly, junctional signaling, and gene expression. Our results demonstrate that Myo9a is a critical regulator of Rho-dependent and -independent signaling mechanisms that guide epithelial differentiation. Moreover, Rho-kinases may represent a new target for therapeutic intervention in some forms of hydrocephalus. INTRODUCTIONThe development and homeostasis of multicellular organisms depends on coordinated cell shape changes that are coupled with alterations in intracellular organization. The dynamic organization of the actin cytoskeleton accounts for many cell shape changes. A multitude of proteins can directly or indirectly modify the dynamics and organization of the actin cytoskeleton. Among these proteins are monomeric GTPases and the superfamily of myosin molecules. The myosin superfamily of actin-based molecular motors is subdivided into more than 30 classes (Odronitz and Kollmar, 2007). The class IX of myosin molecules includes in mammals two members, Myo9a (myr 7) and Myo9b (myr 5), that are both expressed in a number of differentially spliced variants (Bähler, 2008). The Myo9a protein, previously also called myr 7, is expressed during development and in many adult tissues, most abundantly in brain and testis (Chieregatti et al., 1998;Gorman et al., 1999). Class IX myosins comprise in addition to their myosin head domain a tail region that encompasses a C1 domain and a Rho GTPaseactivating protein (RhoGAP) domain (Reinhard et al., 1995;Chieregatti et al., 1998). The RhoGAP domain negatively regulates the monomeric Rho GTPase by accelerating its rate of GTP-hydrolysis, switching it from the active GTP-bound form to the inactive GDP-bound form. The RhoGTPases are known to be important regulators of cell morphogenesis, cell migration, and cell proliferation (Jaffe and Hall, 2005). They are inactivated under spatial and temporal con...

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The Cloning and Developmental Expression of Unconventional Myosin IXA (MYO9A) a Gene in the Bardet–Biedl Syndrome (BBS4) Region at Chromosome 15q22–q23

Cited by 49 publications

References 41 publications

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Motorized RhoGAP myosin IXb (Myo9b) controls cell shape and motility

Myosin IXa Regulates Epithelial Differentiation and Its Deficiency Results in Hydrocephalus

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