We have maintained a transgenic mouse model of hydrocephalus created to overproduce the cytokine, transforming growth factor-β1 (TGF-β1) in the central nervous system (CNS). The aim of the present study was to estimate the embryonic period when the transgenic mice would develop hydrocephalus, by investigating the chronological developmental changes of the cerebral ventricles. Qualitative analysis of ventricular size was performed on sections cut in the coronal plane of embryos at the 15th (E15) and 18th (E18) embryonic days, and postnatal mice aged 4 days (P4). The presence of the TGF-β1 transgene was determined by performing polymerase chain reaction (PCR) analysis. We have examined 24 embryos and 14 postnatal mice. By performing PCR analysis, the TGF-β1 transgene was determined to be present in 16 (42.1%). Five of 16 embryos at E15 carried the transgene, and showed a slight enlargement of the lateral ventricles. Three of 8 embryos at E18 carried the transgene, and had remarkable enlargement of the lateral ventricles. Eight of 14 pups at P4 carried the transgene, and 7 of 8 pups with the transgene developed hydrocephalus. In pups that were positive for the transgene, massive enlargement of the lateral ventricles was observed and there was an associated thinning of the overlying cerebral cortex. These results suggest that congenital hydrocephalus may develop at an important embryonic time period, which coincides with the stage of neural stem cell proliferation and differentiation in the CNS.

Keywords:
Animal model, Cerebral ventricle, Embryo, Hydrocephalus, Transforming growth factor, Transgenic mouse
1.
Massague J: The transforming growth factor-β family. Annu Rev Cell Biol 1990;6:597–641.
2.
Grande JP: Role of transforming growth factor-β in tissue injury and repair. Proc Soc Exp Biol Med 1997;214:27–40.
3.
Galbreath E, Kim SJ, Park K, Brenner M, Messing A: Overexpression of TGF-β1 in the central nervous system of transgenic mice results in hydrocephalus. J Neuropathol Exp Neurol 1995;54:339–349.
4.
Wyss-Coray T, Feng L, Masliah E, Ruppe MD, Lee HS, Toggas SM, Rockenstein EM, Mucke L: Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-β1. Am J Pathol 1995;147:53–67.
5.
Cohen AR, Leifer DW, Zechel M, Flaningan D, Lewin JS, Lust WD: Characterization of a model of hydrocephalus in transgenic mice. J Neurosurg 1999;91:978–988.
6.
Heine UI, Munoz EF, Flanders KC: Role of transforming growth factor-β in the development of the mouse embryo. J Cell Biol 1987;105:2861–2876.
7.
Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlssonn S: Transforming growth factor-β1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 1993;90:770–774.
8.
Blobe GC, Schiemann WP, Lodish HF: Role of transgenic growth factor-β in human disease. N Engl J Med 2000;342:1350–1358.
9.
Attisano L, Wrana JL, Lopez-Casillas F, Massague J: TGF-β receptors and actions. Biochim Biophys Acta 1994;1222:71–80.
10.
Ellingsworth LR, Brennan JE, Fok K, Rosen DM, Bentz H, Piez KA, Seyedin SM: J Biol Chem 1986;261:12363–12367.
11.
Lehnert SA, Akhurst RJ: Embryonic expression pattern of TGF-beta type-1 RNA suggests both paracrine and autocrine mechanisms of action. Development 1988;104:263–273.
12.
Fitzpatrick DR, Denhez F, Kondaiah P, Akhurst RJ: Differential expression of TGF-beta isoforms in murine palatogenesis. Development 1990;109:585–595.
13.
Pelton RW, Dickinson ME, Moses HL, Hogan BL: In situ hybridization analysis of TGF- beta-3 RNA expression during mouse development: Comparative studies with TGF-beta-1 and beta-2. Development 1990;110:609–620.
14.
Pelton RW, Hogan MH, Miller DA, Moses HL: Differential expressing of genes encoding TGFs β1, β2, and β3 during murine palate formation. Dev Biol 1990;141:456–460.
15.
Millan FA, Denhez F, Kondaiah P, Akhurst R: Embryonic gene expression patterns of TGFβ1, β2 and β3 suggest different developmental functions in vivo. Development 1991;111:131–144.
16.
Pelton RW, Saxena B, Jones M, Moses HL, Gold LI: Immunohistochemical localization of TGFβ1, TGFβ2, and TGFβ3 in the mouse embryo: Expression patterns suggest multiple roles during embryonic development. J Cell Biol 1991;115:1091–1105.
17.
Lawler S, Candia AF, Ebner R, Shum L, Lopez AR, Moses HL, Wright CVE, Derynck R: The murine type II TGF-β receptor has a coincident embryonic expression and binding preference for TGF-β1. Development 1994;120:165–175.
18.
Flanders KC, Ludecke G, Engels S: Localization and actions of transforming growth factor-betas in the embryonic nervous system. Development 1991;113:183–191.
19.
Krieglstein K, Rufer M, Suter-Crazzolara C, Unsicker K: Neural functions of the transforming growth factors β. Int J Dev Neurosci 1995;13:301–315.
20.
Green CG: The developmental effects of congenital hydrocephalus in the mouse. Dev Biol 1970;23:585–608.
21.
Border WA, Ruoslahti E: Transforming growth factor-β in disease: The dark side of tissue repair. J Clin Invest 1992;90:1–7.
22.
Bordes WA, Noble NA: Transforming growth factor-β in tissue fibrosis. N Engl J Med 1994;331:1286–1292.
23.
Raghow R: The role of extracellular matrix in postinflammatory wound healing and fibrosis. FASEB J 1994;8:823–831.
24.
Sanderson N, Factor V, Nagy P, Kopp J, Kondaiah P, Wakefield L, Roberts AB, Sporn MB, Thorgeirsson SS: Hepatic expression of mature transforming growth factor-β1 in transgenic mice results in multiple tissue lesions. Proc Natl Acad Sci USA 1995;92:2572–2576.
25.
Kopp JB, Factor VM, Mozes M, Nagy P, Sanderson N, Bottinger EP, Klotman PE, Thorgeirsson SS: Transgenic mice with increased plasma levels of TGF-β1 progressive renal disease. Lab Invest 1996;74:991–1003.
26.
Singer AJ, Clark RAF: Cutaneous wound healing. N Engl J Med 1999;341:738–746.
27.
Johnson MD, Gold LI, Moses HL: Evidence for transforming growth factor expression in human leptomeningeal cells and transforming growth factor-β-like activity in human cerebrospinal fluid. Lab Invest 1992;67:360–368.
28.
Whitelaw A, Christie S, Pople I: Transforming growth factor-β1: A possible signal molecule for posthemorrhagic hydrocephalus? Pediatr Res 1999;46:576–580.
29.
Kitazawa K, Tada T: Elevation of transforming growth factor-β1 level in cerebrospinal fluid of patients with communicating hydrocephalus after subarachnoid hemorrhage. Stroke 1994;25:1400–1404.
30.
Tada T, Kitazawa K, Kobayashi S: Induction of communicating hydrocephalus in mice by intrathecal injection of human recombinant transforming growth factor-β1. J Neuroimmunol 1994;50:153–158.
31.
Nitta J, Tada T: Ultramicroscopic structures of the leptomeninx of mice with communicating hydrocephalus induced by human recombinant transforming growth factor-β1. Neurol Med Chir (Tokyo) 1998;38:819–825.
32.
Wilson DB: Cellular proliferation in the exencephalic brain of the mouse embryo. Brain Res 1980;195:139–148.
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2000
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