QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 20, Issue 24, 5074-5085, December 15, 2009

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E09-04-0291v1 20/24/5074    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Abouhamed, M. Articles by Bähler, M. PubMed PubMed Citation Articles by Abouhamed, M. Articles by Bähler, M.

Myosin IXa Regulates Epithelial Differentiation and Its Deficiency Results in Hydrocephalus

Marouan Abouhamed^*,, Kay Grobe^*,,, Isabelle V. Leefa Chong San, Sabine Thelen^*, Ulrike Honnert^*, Maria S. Balda, Karl Matter, and Martin Bähler^*

*Institute of General Zoology and Genetics, Westfalian Wilhelms University, 48149 Münster, Germany; and Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom

Submitted April 10, 2009; Revised October 5, 2009; Accepted October 7, 2009
Monitoring Editor: Josephine C. Adams

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.

These authors contributed equally to this work.

Present address: Physiological Chemistry and Pathobiochemistry, University of Münster, Münster D-48149, Germany.

Address correspondence to: Martin Bähler (baehler{at}uni-muenster.de).

Abbreviations used: CSF, cerebrospinal fluid; Myo9a, myosin IXa; RhoGAP, Rho GTPase-activating protein; ROCK, Rho-kinase; WT, wild type.