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. 2006 Apr 5;14(3):312–316. doi: 10.1111/j.1750-3639.2004.tb00070.x

Insights into the Pathogenesis of Hydrocephalus from Transgenic and Experimental Animal Models

Leslie Crews 1, Tony Wyss‐Coray 2,3, Eliezer Masliah 1,4,
PMCID: PMC8095739  PMID: 15446587

Abstract

Hydrocephalus is a progressive brain disorder characterized by abnormalities in the flow of cerebrospinal fluid (CSF) and ventricular dilatation that leads to cerebral atrophy, and if left untreated, can be fatal. Genetic mutations, congenital malformations, infectious diseases, intracerebral hemorrhages and tumors are common conditions resulting in hydrocephalus. Although the causes of obstructive hydrocephalus are better understood, the mechanisms resulting in chronic, progressive communicating congenital and acquired hydrocephalus are less well understood. In this regard, recent studies in transgenic (tg) mice suggest that increased expression of cytokines such as TGF‐β1 might play an important role by disrupting the vascular extracellular matrix (ECM) remodeling, promoting hemorrhages, and altering the reabsorption of CSF. In this context, the main objective of this manuscript is to provide an overview on the cellular and molecular mechanisms of hydrocephalus based on studies derived from tg and experimental animal models.

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REFERENCES

  • 1. Al‐Shroof M, Karnik AM, Karnik AA, Longshore J, Sliman NA, Khan FA (2001) Ciliary dyskinesia associated with hydrocephalus and mental retardation in a Jordanian family. Mayo Clin Proc 76:1219–1224. [DOI] [PubMed] [Google Scholar]
  • 2. Ata AK, Funa K, Olsson Y (1997) Expression of various TGF‐beta isoforms and type I receptor in necrotizing human brain lesions. Acta Neuropathol(Berl) 93:326–333. [DOI] [PubMed] [Google Scholar]
  • 3. Benveniste E (1998) Cytokine actions in the central nervous system. CytoGrowth Factor Rev 9:259–275. [DOI] [PubMed] [Google Scholar]
  • 4. Bottner M, Unsicker K, Suter‐Crazzolara C (1996) Expression of TGF‐beta type II receptor mRNA in the CNS. Neuroreport 7:2903–2907. [DOI] [PubMed] [Google Scholar]
  • 5. Brady TB, Kramer RL, Qureshi F, Feldman B, Kupsky WJ, Johnson MP, Evans MI (1999) Ontogeny of recurrent hydrocephalus: presentation in three fetuses in one consanguineous family. Fetal Diagn Ther 14:198–200. [DOI] [PubMed] [Google Scholar]
  • 6. Cohen AR, Leifer DW, Zechel M, Flaningan DP, Lewin JS, Lust WD (1999) Characterization of a model of hydrocephalus in transgenic mice. J Neurosurg 91:978–988. [DOI] [PubMed] [Google Scholar]
  • 7. da Cunha A, Jefferson J, Jackson R, Vitkovic L (1993) Glial cell‐specific mechanisms of TGF‐beta 1 induction by IL‐1 in cerebral cortex. JNeuroimmunol 42:71–86. [DOI] [PubMed] [Google Scholar]
  • 8. Davy BE, Robinson ML (2003) Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene. Hum Mol Genet 12:1163–1170. [DOI] [PubMed] [Google Scholar]
  • 9. Del Bigio MR (1993) Neuropathological changes caused by hydrocephalus. Acta Neuropathol (Berl) 85:573–585. [DOI] [PubMed] [Google Scholar]
  • 10. Del Bigio MR, Bruni JE (1988) Changes in periventricular vasculature of rabbit brain following induction of hydrocephalus and after shunting. J Neurosurg 69:115–120. [DOI] [PubMed] [Google Scholar]
  • 11. Del Bigio MR, Wilson MJ, Enno T (2003) Chronic hydrocephalus in rats and humans: white matter loss and behavior changes. Ann Neurol 53:337–346. [DOI] [PubMed] [Google Scholar]
  • 12. Del Bigio MR, Zhang YW (1998) Cell death, axonal damage, and cell birth in the immature rat brain following induction of hydrocephalus. Exp Neurol 154:157–169. [DOI] [PubMed] [Google Scholar]
  • 13. Dixon WE, Heller H (1932) Experimentel Hypertonie durch Erhohung des intrakraniellen Druckes. Arch Exp Pathol Pharmacol 166:265–275. [Google Scholar]
  • 14. Flood C, Akinwunmi J, Lagord C, Daniel M, Berry M, Jackowski A, Logan A (2001) Transforming grow factor‐beta1 in the cerebrospinal fluid of patients with subarachnoid hemorrhage: titers derived from exogenous and endogenous sources. J Cereb Blood Flow Metab 21:157–162. [DOI] [PubMed] [Google Scholar]
  • 15. Gadsdon DR, Variend S, Emery JL (1979) Myelination of the corpus callosum. II. The effect of relief of hydrocephalus upon the processes of myelination. Z Kinderchir Grenzgeb 28:314–321. [PubMed] [Google Scholar]
  • 16. Galbreath E, Kim S‐J, Park K, Brenner M, Messing A (1995) Overexpression of TGF‐β1 in the central nervous system of transgenic mice results in hydrocephalus. JNeuropatholExpNeurol 54:339–349. [DOI] [PubMed] [Google Scholar]
  • 17. Game K, Friedman JM, Paradice B, Norman MG (1989) Fetal growth retardation, hydrocephalus, hypoplastic multilobed lungs, and other anomalies in 4 sibs. Am J Med Genet 33:276–279. [DOI] [PubMed] [Google Scholar]
  • 18. Greenstone M, Cole PJ (1984) Primary ciliary dyskinesia. Arch Dis Child 59:704–706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Gruneberg H (1943) Two new mutant genes in the house mouse. J Genet 45:22–28. [Google Scholar]
  • 20. Kitazawa K, Tada T (1994) Elevation of transforming growth factor‐beta 1 level in cerebrospinal fluid of patients with communicating hydrocephalus after subarachnoid hemorrhage. Stroke 25:1400–1404. [DOI] [PubMed] [Google Scholar]
  • 21. Kondziella D, Ludemann W, Brinker T, Sletvold O, Sonnewald U (2002) Alterations in brain metabolism, CNS morphology and CSF dynamics in adult rats with kaolin‐induced hydrocephalus. Brain Res 927:35–41. [DOI] [PubMed] [Google Scholar]
  • 22. Lindholm D, Castren E, Kiefer R, Zafra F, Thoenen H (1992) Transforming growth factor‐β1 in the rat brain: Increase after injury and inhibition of astrocyte proliferation. JCell Biol 117: 395–400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Lippa C, Flanders K, Kim E, Croul S (1998) TGF‐β receptors‐I and ‐II immunoexpression in Alzheimer's disease: A comparison with aging and progressive supranuclear palsy. NeurobiolAging 19:527–533. [DOI] [PubMed] [Google Scholar]
  • 24. Logan A, Frautschy S, Gonzalez A‐M, Sporn M, Baird A (1992) Enhanced expression of transforming growth factor β1 in the rat brain after a localised cerebral injury. Brain Res 587:216–225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Massague J (1998) TGF‐beta signal transduction. Annu Rev Biochem 67:753–791. [DOI] [PubMed] [Google Scholar]
  • 26. Mattson M, Barger S, Furukawa K, Bruce A, Wyss‐Coray T, Mark R, Mucke L (1997) Cellular signaling roles of TGFβ, TNFα and βAPP in brain injury responses and Alzheimer's disease. Brain ResRev 23:46–61. [DOI] [PubMed] [Google Scholar]
  • 27. Mozes MM, Bottinger EP, Jacot TA, Kopp JB (1999) Renal expression of fibrotic matrix proteins and of transforming growth factor‐beta (TGF‐beta) isoforms in TGF‐beta transgenic mice. J Am Soc Nephrol 10:271–280. [DOI] [PubMed] [Google Scholar]
  • 28. Norman MG, McGillivray B (1988) Fetal neuropathology of proliferative vasculopathy and hydranencephaly‐hydrocephaly with multiple limb pterygia. Pediatr Neurosci 14:301–306. [DOI] [PubMed] [Google Scholar]
  • 29. Picco P, Leveratto L, Cama A, Vigliarolo MA, Levato GL, Gattorno M, Zammarchi E, Donati MA (1993) Immotile cilia syndrome associated with hydrocephalus and precocious puberty: a case report. Eur J Pediatr Surg 3 Suppl 1:20–21. [PubMed] [Google Scholar]
  • 30. Prehn J, Bindokas V, Jordan J, Galindo M, Ghadge G, Roos R, Boise L, Thompson C, Krajewski S, Reed J, et al (1996) Protective effect of transforming growth factor β1 on β‐amyloid neurotoxicity in rat hippocampal neurons. Mol-Pharmacol 49:31–328. [PubMed] [Google Scholar]
  • 31. Raimondi AJ, Bailey OT, McLone DG, Lawson RF, Echeverry A (1973) The pathophysiology and morphology of murine hydrocephalus in Hy‐3 and Ch mutants. Surg Neurol 1:50–55. [PubMed] [Google Scholar]
  • 32. Roberts A, Sporn M (1996) Transforming growth factor‐β. In The molecular and cellular biology of wound repair, Clark R (eds). Plenum Press: New York . pp. 275–308. [Google Scholar]
  • 33. Robinson ML, Allen CE, Davy BE, Durfee WJ, Elder FF, Elliott CS, Harrison WR (2002) Genetic mapping of an insertional hydrocephalus‐inducing mutation allelic to hy3. Mamm Genome 13:625–632. [DOI] [PubMed] [Google Scholar]
  • 34. Slotkin TA, Wang XF, Symonds HS, Seidler FJ (1997) Expression of mRNAs coding for the transforming growth factor‐beta receptors in brain regions of euthyroid and hypothyroid neonatal rats and in adult brain. Brain Res Dev Brain Res 99:61–65. [DOI] [PubMed] [Google Scholar]
  • 35. Tada T, Kanaji M, Kobayashi S (1994) Induction of communicating hydrocephalus in mice by intrathecal injection of human recombinant transforming growth factor‐beta 1. J Neuroimmunol 50:153–158. [DOI] [PubMed] [Google Scholar]
  • 36. Takizawa T, Tada T, Kitazawa K, Tanaka Y, Hongo K, Kameko M, Uemura KI (2001) Inflammatory cytokine cascade released by leukocytes in cerebrospinal fluid after subarachnoid hemorrhage. Neurol Res 23:724–730. [DOI] [PubMed] [Google Scholar]
  • 37. Torikata C, Kijimoto C, Koto M (1991) Ultra‐structure of respiratory cilia of WIC‐Hyd male rats. An animal model for human immotile cilia syndrome. Am J Pathol 138:341–347. [PMC free article] [PubMed] [Google Scholar]
  • 38. Tubbs RS, Banks JT, Soleau S, Smyth MD, Wellons JC, 3rd , Blount JP, Grabb PA, Oakes WJ (2004) Complications of ventriculosubgaleal shunts in infants and children. Childs Nerv Syst. . [DOI] [PubMed]
  • 39. Ulfig N, Bohl J, Neudorfer F, Rezaie P (2004) Brain macrophages and microglia in human fetal hydrocephalus. Brain Dev 26:307–315. [DOI] [PubMed] [Google Scholar]
  • 40. Unsicker K, Flanders K, Cissel D, Lafyatis R, Sporn M (1991) Transforming growth factor beta isoforms in the adult rat central and peripheral nervous system. Neuroscience 44:613–625. [DOI] [PubMed] [Google Scholar]
  • 41. van Camp G, Vits L, Coucke P, Lyonnet S, Schrander‐Stumpel C, Darby J, Holden J, Munnich A, Willems PJ (1993) A duplication in the L1 CAM gene associated with X‐linked hydrocephalus. Nat Genet 4:421–425. [DOI] [PubMed] [Google Scholar]
  • 42. Verhagen WI, Bartels RH, Fransen E, van Camp G, Renier WO, Grotenhuis JA (1998) Familial congenital hydrocephalus and aqueduct stenosis with probably autosomal dominant inheritance and variable expression. J Neurol Sci 158:101–105. [DOI] [PubMed] [Google Scholar]
  • 43. Wang YQ, Sizeland A, Wang XF, Sassoon D (1995) Restricted expression of type‐II TGF beta receptor in murine embryonic development suggests a central role in tissue modeling and CNS patterning. Mech Dev 52:275–289. [DOI] [PubMed] [Google Scholar]
  • 44. Weller S, Gartner J (2001) Genetic and clinical aspects of X‐linked hydrocephalus (L1 disease): Mutations in the L1 CAM gene. Hum Mutat 18: 1–12. [DOI] [PubMed] [Google Scholar]
  • 45. Whitelaw A, Christie S, Pople I (1999) Transforming growth factor‐beta1: a possible signal molecule for posthemorrhagic hydrocephalus Pediatr Res 46:576–580. [DOI] [PubMed] [Google Scholar]
  • 46. Wyss‐Coray T, Feng L, Masliah E, Ruppe M, Toggas S, Rockenstein E, Mucke L (1995) Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor β1. AmJPathol 147:53–67. [PMC free article] [PubMed] [Google Scholar]
  • 47. Wyss‐Coray T, Masliah E, Mallory M, McConlogue L, Johnson‐Wood K, Campagno F, Lin C, Samuels I, Mucke L (1997) Amyloidogenic role of transforming growth factor β1 in transgenic mice and Alzheimer's disease. Nature 389:603–606. [DOI] [PubMed] [Google Scholar]
  • 48. Wyss‐Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, Masliah E (2002) Prominent neurodegeneration and increased plaque formation in complement‐inhibited Alzheimer's mice. Proc Natl Acad Sci U S A 99:10837–10842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Zechel J, Gohil H, Lust WD, Cohen A (2002) Alterations in matrix metalloproteinase‐9 levels and tissue inhibitor of matrix metalloprotein‐ases‐1 expression in a transforming growth factor‐beta transgenic model of hydrocephalus. J Neurosci Res 69:662–668. [DOI] [PubMed] [Google Scholar]

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