- Short paper
- Open Access
Hydrocephalus caused by conditional ablation of the Pten or beta-catenin gene
© Ohtoshi; licensee BioMed Central Ltd. 2008
Received: 15 August 2008
Accepted: 18 October 2008
Published: 18 October 2008
To investigate the roles of Pten and β-Catenin in the midbrain, either the Pten gene or the β-catenin gene was conditionally ablated, using Dmbx1 (diencephalon/mesencephalon-expressed brain homeobox gene 1)-Cre mice. Homozygous disruption of the Pten or β-catenin gene in Dmbx1-expressing cells caused severe hydrocephalus and mortality during the postnatal period. Conditional deletion of Pten resulted in enlargement of midbrain structures. β-catenin conditional mutant mice showed malformation of the superior and inferior colliculi and stenosis of the midbrain aqueduct. These results demonstrate that both Pten and β-Catenin are essential for proper midbrain development, and provide the direct evidence that mutations of both Pten and β-catenin lead to hydrocephalus.
Congenital hydrocephalus is one of the most common birth defects associated with malformation and/or malfunction of the brain. Although genetic factors are likely to be involved in pathogenesis of hydrocephalus, molecular etiology that causes congenital hydrocephalus is poorly understood, partly due to involvement of multiple genes . Recent studies implicate the genes Pten and β-catenin in association with hydrocephalus [2–4]; however, it is not clear whether mutations of these genes are causally involved in hydrocephalus. This report shows that conditional inactivation of either Pten or β-catenin causes hydrocephalus in mice. Although the relationship between Pten and β-catenin has been intensively investigated in cancer cells in relation to tumorigenesis, it is not known how these genes interact, in terms of brain development.
Pten is a phosphatase that plays critical roles in intracellular signal transduction through dephosphorylation of substrates such as Akt and S6 kinases . Although Pten is well known as a tumor suppressor gene, it is also involved in normal cellular proliferation/differentiation and function. Conditional ablation of the Pten gene by Nestin-Cre mice revealed that Pten is important for proper neural stem cell proliferation and maintenance of soma size . Ablation of Pten by Gfap-Cre mice causes neuronal hypertrophy and behavioral abnormalities similar to Lhermitte-Duclos disease [7, 8].
β-Catenin acts in both cadherin-catenin cell adhesion and Wnt signalling pathways and plays a crucial role in multiple physiological processes such as embryogenesis and cancer. Deletion of β-catenin in Wnt1-expressing cells demonstrated its essential function in embryonic brain development . Inactivation of β-catenin by Nestin-Cre mice revealed that β-Catenin is also required for morphogenesis of the cerebellum .
These results suggest that Pten and β-Catenin are required for brain formation and their loss of function results in aberrant brain development, progressive hydrocephalus and the postnatal lethality. Recently, a mutation of the PTEN gene is implicated in association with human VATER-hydrocephalus syndrome . In hyh (hydrocephalus with hop gait) mutant mice, abnormal localization of cell fate determinant proteins such as β-Catenin and E-cadherin was observed in neuroepithelial cells . Mislocalization of β-Catenin and N-cadherin was also observed in Dlg5 mutant mice that manifest obstructive hydrocephalus . These observations suggest that Pten and β-Catenin are associated with congenital hydrocephalus. Here, direct evidence demonstrates that loss of Pten or β-Catenin causes hydrocephalus in mice.
Although phenotypical manifestations such as dilated ventricles, excessive CSF and mortality are commonly observed in animal models with both communicating and non-communicating hydrocephalus, the molecular and cellular etiologies are diverse. The hyh mutant mice carry a mutation in the α-SNAP gene that encodes a protein involved in SNAP receptor (SNARE)-mediated apical membrane transport of cadherin/catenin complexes in polarized epithelial cells . Dlg5 is also required for SNARE-dependent intracellular trafficking of cadherin/catenin molecules and disruption of Dlg5 results in collapse of epithelial tubes . Therefore, loss of β-Catenin in epithelial cells likely caused the stenosis of the midbrain aqueduct in the β-cateninloxP/loxP; Dmbx1-Cre mice. Alternatively, the aqueduct closure could be secondary to disturbance of CSF flow as seen in Hydrocephalus Texas (H-Tx) rats that show abnormalities in secretory ependymal cells of the subcommissural organ . Severely affected H-Tx rats die at 4–6 weeks whereas the β-cateninloxP/loxP; Dmbx1-Cre mice did not survive beyond 4 weeks. The hy3 mice carry a mutation in the Hydin gene that is expressed in the ciliated ependymal cells and die before 7 weeks of age . They first develop a defect in CSF reabsorption and later a blockage within the cerebral aqueduct. Further investigations are needed to elucidate the pathogenic mechanisms leading to hydrocephalus in the PtenloxP/loxP; Dmbx1-Cre and β-cateninloxP/loxP; Dmbx1-Cre mice. These mutant mice will serve as a novel model for congenital hydrocephalus and provide a novel opportunity to investigate molecular etiology of hydrocephalus.
I am grateful to Dong-Woo Hwang for histological analyses. This study was initiated at Children's Research Institute (Columbus, Ohio). I thank Hope-tecture Research Institute (Hyogo, Japan) for support.
- Zhang J, Williams MA, Rigamonti D: Genetics of human hydrocephalus. J Neurol. 2006, 253: 1255-1266. 10.1007/s00415-006-0245-5.PubMed CentralView ArticlePubMedGoogle Scholar
- Reardon W, Zhou XP, Eng C: A novel germline mutation of the PTEN gene in a patient with macrocephaly, ventricular dilatation, and features of VATER association. J Med Genet. 2001, 38: 820-823. 10.1136/jmg.38.12.820.PubMed CentralView ArticlePubMedGoogle Scholar
- Chae TH, Kim S, Marz KE, Hanson PI, Walsh CA: The hyh mutation uncovers roles of αSnap in apical protein localization and control of neural cell fate. Nat Genet. 2004, 36: 264-270. 10.1038/ng1302.View ArticlePubMedGoogle Scholar
- Nechiporuk T, Fernandez TE, Vasioukhin V: Failure of epithelial tube maintenance causes hydrocephalus and renal cysts in Dlg5-/- mice. Dev Cell. 2007, 13: 338-350. 10.1016/j.devcel.2007.07.017.PubMed CentralView ArticlePubMedGoogle Scholar
- Manning BD: Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol. 2004, 167: 399-403. 10.1083/jcb.200408161.PubMed CentralView ArticlePubMedGoogle Scholar
- Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA, Kornblum HI, Liu X, Wu H: Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science. 2001, 294: 2186-2189. 10.1126/science.1065518.View ArticlePubMedGoogle Scholar
- Kwon CH, Zhu X, Zhang J, Knoop LL, Tharp R, Smeyne RJ, Eberhart CG, Burger PC, Baker SJ: Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet. 2001, 29: 404-411. 10.1038/ng781.View ArticlePubMedGoogle Scholar
- Backman SA, Stambolic V, Suzuki A, Haight J, Elia A, Pretorius J, Tsao MS, Shannon P, Bolon B, Ivy GO, Mak TW: Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet. 2001, 29: 396-403. 10.1038/ng782.View ArticlePubMedGoogle Scholar
- Brault V, Moore R, Kutsch S, Ishibashi M, Rowitch DH, McMahon AP, Sommer L, Boussadia O, Kemler R: Inactivation of the β-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. Development. 2001, 128: 1253-1264.PubMedGoogle Scholar
- Schüller U, Rowitch DH: β-catenin function is required for cerebellar morphogenesis. Brain Res. 2007, 1140: 161-169. 10.1016/j.brainres.2006.05.105.View ArticlePubMedGoogle Scholar
- Ohtoshi A, Bradley A, Behringer RR, Nishijima I: Generation and maintenance of Dmbx1 gene-targeted mutant alleles. Mamm Genome. 2006, 17: 744-750. 10.1007/s00335-006-0021-y.View ArticlePubMedGoogle Scholar
- Somera KC, Jones HC: Reduced subcommissural organ glycoprotein immunoreactivity precedes aqueduct closure and ventricular dilatation in H-Tx rat hydrocephalus. Cell Tissue Res. 2004, 315: 361-373. 10.1007/s00441-003-0843-9.View ArticlePubMedGoogle Scholar
- Davy BE, Robinson ML: Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene. Hum Mol Genet. 2003, 12: 1163-1170. 10.1093/hmg/ddg122.View ArticlePubMedGoogle Scholar
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