title: Characterization of a model of hydrocephalus in transgenic mice.
abstract: OBJECTIVE
  The purpose of this study was to elucidate the pathophysiological characteristics of hydrocephalus in a new transgenic model of mice created to overproduce the cytokine transforming growth factor-beta1 (TGFbeta1) in the central nervous system (CNS).
  
  
  METHODS
  Galbreath and colleagues generated transgenic mice that overexpressed TGFbeta1 in the CNS in an effort to examine the role of this cytokine in the response of astrocytes to injury. Unexpectedly, the animals developed severe hydrocephalus and died. The authors have perpetuated this transgenic colony to serve as a model of congenital hydrocephalus, breeding asymptomatic carrier males that are heterozygous for the transgene with wild-type females. One hundred twelve (49.6%) of 226 mice developed clinical manifestations of hydrocephalus, characterized by dorsal doming of the calvaria, spasticity, limb tremors, ataxia, and, ultimately, death. The presence of the TGFbeta1 transgene was determined by performing polymerase chain reaction (PCR) analysis of sample tail slices. Animals with the hydrocephalic phenotype consistently carried the transgene, although some animals with the transgene did not develop hydrocephalus. Animals without the transgene did not develop hydrocephalus. Alterations in brain structure were characterized using magnetic resonance (MR) imaging, gross and light microscopic analysis, and immunocytochemical studies. Magnetic resonance imaging readily distinguished hydrocephalic animals from nonhydrocephalic controls and demonstrated an obstruction at the outlets of the fourth ventricle. Gross and light microscopic examination confirmed the MR findings. The results of immunofluorescent staining of brain tissue slices revealed the presence of the TGFbeta1 cytokine and its receptor preferentially in the meninges and subarachnoid space in both hydrocephalic and control mice. Reverse transcriptase-PCR analysis demonstrated tissue-specific expression of the TGFbeta1, gene in the brains of transgenic mice, and enzyme-linked immunosorbent assay confirmed overexpression of the TGFbeta1 cytokine in brain, cerebrospinal fluid, and plasma.
  
  
  CONCLUSIONS
  The transgenic murine model provides a reproducible representation of congenital hydrocephalus. The authors hypothesize that overexpression of TGFbeta1 in the CNS causes hydrocephalus by altering the environment of the extracellular matrix and interfering with the circulation of cerebrospinal fluid. A model of hydrocephalus in which the genetic basis is known should be useful for evaluating hypotheses regarding the pathogenesis of this disorder and should also help in the search for new treatment strategies.
authors.affiliation: Rainbow Babies and Children's Hospital, Department of Neurological Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Cohen
authors.forename: D W
authors.initials: DW
authors.lastname: Leifer
authors.forename: M
authors.initials: M
authors.lastname: Zechel
authors.forename: D P
authors.initials: DP
authors.lastname: Flaningan
authors.forename: J S
authors.initials: JS
authors.lastname: Lewin
authors.forename: W D
authors.initials: WD
authors.lastname: Lust
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006580:Genetic Carrier Screening; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology
chemical_list: D016212:Transforming Growth Factor beta