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Genetic Deletion of Rnd3 Results in Aqueductal Stenosis Leading to Hydrocephalus Through Up-Regulation of Notch Signaling

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Genetic Deletion of Rnd3 Results in Aqueductal Stenosis Leading to Hydrocephalus Through Up-Regulation of Notch Signaling Genetic deletion of Rnd3 results in aqueductal stenosis leading to hydrocephalus through up-regulation of Notch signaling Xi Lina, Baohui Liub, Xiangsheng Yanga, Xiaojing Yuea, Lixia Diaoc, Jing Wangc, and Jiang Changa,1 aInstitute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030; bDepartment of Neurosurgery, Renmin Hospital, Wuhan University, Wuhan, Hubei 430060, China; and cDepartment of Bioinformatics and Computational Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 Edited by Iva Greenwald, Columbia University, New York, NY, and approved April 3, 2013 (received for review November 27, 2012) Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of 10). Initial studies of Rnd3 focused mainly on its inhibitory effect the small Rho GTPase family, is involved in the regulation of cell actin on Rho kinase-mediated biological functions, including actin cy- cytoskeleton dynamics, cell migration, and proliferation through the toskeleton formation, myosin light chain phosphatase phosphor- Rho kinase-dependent signaling pathway. We report a role of Rnd3 ylation, and apoptosis (9–11). Recent studies have identified Rnd3 in the pathogenesis of hydrocephalus disorder. Mice with Rnd3 ge- as essential in mouse neuron development through its negative netic deletion developed severe obstructive hydrocephalus with en- regulation of the Rho signaling pathway (12, 13). largement of the lateral and third ventricles, but not of the fourth In this study, we demonstrated a different function of Rnd3. ventricles. The cerebral aqueducts in Rnd3-null mice were partially or Mice with a genetic deletion of Rnd3 developed aqueductal ste- completely blocked by the overgrowth of ependymal epithelia. We nosis, which led to the development of obstructive hydrocephalus examined the molecular mechanism contributing to this Rnd3-defi- owing to hyperplasia of ependymal cells in the aqueducts. We also ciency–mediated hydrocephalus and found that Rnd3 is a regulator identified the molecular mechanism of Rnd3 deficiency-induced of Notch signaling. Rnd3 deficiency, through either gene deletion or hydrocephalus and demonstrated that Rnd3 is a regulator of Notch siRNA knockdown, resulted in a decrease in Notch intracellular do- signaling. Rnd3 deficiency in animal studies and down-regulation main (NICD) protein degradation. However, there was no correlated in cell culture experiments were associated with obvious decreases NEUROSCIENCE change in mRNA change, which in turn led to an increase in NICD in Notch intracellular domain (NICD) degradation, which in turn protein levels. Immunoprecipitation analysis demonstrated that led to an increase in NICD protein levels. This eventually pro- Rnd3 and NICD physically interacted, and that down-regulation of moted Notch signaling activity and facilitated aqueduct ependymal Rnd3 attenuated NICD protein ubiquitination. This eventually en- cell proliferation, resulting in aqueductal stenosis and the de- hanced Notch signaling activity and promoted aberrant growth of velopment of congenital hydrocephalus. The pathogenesis of hy- aqueduct ependymal cells, resulting in aqueduct stenosis and the drocephalus was curtailed by the inhibition of Notch activity. development of congenital hydrocephalus. Inhibition of Notch activ- ity rescued the hydrocephalus disorder in the mutant animals. Results High Expression of Rnd3 Was Detected in Mouse Brains, Particularly in developmental brain defect | genetic mouse model | post-translational Ependymal Cells Lining Aqueducts and Ventricles. The generation of fi modi cation Rnd3 KO mice is described in Materials and Methods.Thetargeting vector carried a β-gal expression cassette with an internal ribosomal he cerebrospinal fluid (CSF) flow tract is a dynamic circulatory entry site. The endogenous levels of Rnd3 were detected by beta- Tsystem that supplies the brain with essential nutrients and galactosidase (lacZ) staining, showing the universal expression of growth factors throughout development and into adulthood (1). Rnd3, with high expression levels in the CNS (Fig. 1A). Rnd3 Ependymal cells, specified epithelial cells that line the aqueduct transcript levels in various organs were assessed by quantitative and cerebral ventricles of mammalian species, make up the CSF PCR (qPCR) and found to be consistent with the lacZ staining (Fig. tract and propel CSF flow (2, 3). Malformation of the ependymal 1B). Immunohistochemistry analysis revealed enriched expression epithelium can lead to failure of cerebral irrigation and a buildup of Rnd3 in the ependymal cells lining the aqueductal lumina (Fig. 1 of CSF in the ventricular cavities of the brain, a pathological C and D) and the inner ventricle walls (Fig. 1 E and F). condition known as hydrocephalus. Hydrocephalus in humans is a severe neurologic disorder Severe Hydrocephalus Was Caused by Aqueductal Stenosis Through characterized by an excessive accumulation of CSF in the brain. It Aberrant Growth of Ependymal Cells as a Result of Genetic Deletion − − affects approximately 1 in every 500 children, based on estimates of Rnd3. Rnd3 / mice exhibited a dome-shaped skull (Fig. 2A). from the National Institute of Neurological Disorders and Stroke. A large amount of CSF drained out of the mutant mouse brain The precise causes of hydrocephalus remain largely unknown. during isolation (Fig. 2B). Significantly enlarged lateral ventricles Accumulating evidence suggests that genetic factors are critical to and remarkable thinning of the occipital cortex were observed the pathogenesis of hydrocephalus. Congenital hydrocephalus, (Fig. 2C) and quantified (Fig. 2D). Further dissections revealed caused by genetic abnormalities, is the most common type. the extremely dilated or broken third ventricles (Fig. 3 A and B) Aqueductal stenosis is the major contributing factor in congenital along with the narrowed or even disconnected aqueduct (Fig. 3 C hydrocephalus, with an prevalence of 0.1–0.3% of all live births (4). At least nine genes have been identified as closely associated with the pathogenesis of congenital hydrocephalus in animal Author contributions: X.L. and J.C. designed research; X.L., B.L., X. Yang, and X. Yue per- studies, but few of these genes have been verified in humans (5–8). formed research; X.L., L.D., J.W., and J.C. analyzed data; and X.L. and J.C. wrote the paper. Continued identification of new genes/loci linked to congenital The authors declare no conflict of interest. hydrocephalus will expand our knowledge of the genetic compo- This article is a PNAS Direct Submission. nents of this disorder. 1To whom correspondence should be addressed. E-mail: [email protected]. Rho family GTPase 3 (Rnd3, also known as RhoE) was origi- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. nally defined as a repressor of Rho protein kinase 1 (ROCK1) (9, 1073/pnas.1219995110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1219995110 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 elevated (Fig. 4E). These data suggest that NICD is under post- translational regulation through Rnd3. Given that the ubiquitin-proteasome system (UPS) is a critical posttranslational regulation mechanism for NICD, we investigated whether Rnd3 plays a role in UPS-mediated NICD degradation. We first examined the expression profiles of the two proteins, and found that both Rnd3 and Notch1 receptors were highly expressed in mouse aqueductal ependyma (Fig. 5A). We then explored the interaction of Rnd3 and NICD ex vivo by cotransfection of myc- Rnd3 and flag-NICD in HEK293T cells, followed by mutual coimmunoprecipitation (Fig. 5 B and C). To evaluate the bi- ological significance of the interaction of these two proteins, we assessed the levels of NICD protein along with the increase in Rnd3 expression. Immunoblot analysis revealed decreased NICD protein levels when the cells expressed higher levels of Rnd3 (Fig. 5D, lanes 1–3). This process was significantly attenuated by treatment with a proteasome inhibitor, MG132 (Fig. 5D,lanes 4–6). The enhanced NICD degradation after the introduction of Rnd3 was verified by cycloheximide chase analysis. Lower en- dogenous NICD protein levels were observed in cells transfected with the Rnd3 expression vector compared with control cells (Fig. 5E). These data provide evidence that Rnd3 interacts with NICD and promotes UPS-mediated NICD degradation. Fig. 1. Expression of Rnd3 is universal and enriched in the CNS, with the highest levels in the ependymal cells lining the aqueduct, lateral ventricle, Inhibition of Notch Signaling Blocked Rnd3 Deficiency-Induced and third ventricle. (A) LacZ staining displayed Rnd3 expression in an E9.5 mouse. (B) Transcript levels of Rnd3 were quantified by qPCR analysis. (C and Aqueductal Ependymal Cell Aberrant Growth and Prevented Hydro- D) Enriched expression of Rnd3 was detected in ependymal cells at an aq- cephalus in Rnd3-Null Mice. Consistent with our early findings in- ueduct (Aq) region shown by lacZ staining (C, arrow) and by immunostaining dicating the overgrowth of aqueductal ependymal cells (Fig. 3I), (D). (E and F) Ependymal cells at lateral ventricle (LV) (E) and third ventricle we detected a more intense immunostaining of phosphorylated (3V) (F) also displayed high expression levels of Rnd3. qPCR data were His3 (p-His3) in aqueducts of the mutant mice compared with pooled from four mice, with analyses for each organ done in triplicate. di, WT mice (Fig. 6A). To investigate whether the
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