Characterization of a model of hydrocephalus in transgenic mice

Object. The purpose of this study was to elucidate the pathophysiological c haracteristics of hydrocephalus in a new transgenic model of mice created t o overproduce the cytokine transforming growth factor-beta(1) (TGF beta(1)) in the central nervous system (CNS). Methods. Galbreath and colleagues generated transgenic mice that overexpres sed TGF beta(1) in the CNS in an effort to examine the role of this cytokin e in the response of astrocytes to injury. Unexpectedly, the animals develo ped severe hydrocephalus and died. The authors have perpetuated this transg enic colony to serve as a model of congenital hydrocephalus, breeding asymp tomatic carrier males that are heterozygous for the transgene with wild-typ e 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 TGF beta (1) transgene was determined by performing polymerase chain reaction (PCR) analysis of sample tail slices. Animals with the hydrocephalic phenotype co nsistently carried the transgene, although some animals with the transgene did not develop hydrocephalus. Animals without the transgene did not develo p 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 ani mals from nonhydrocephalic controls and demonstrated an obstruction at the outlets of the fourth ventricle. Gross and light microscopic examination co nfirmed the MR findings. The results of immunofluorescent staining of brain tissue slices revealed the presence of the TGF beta(1) cytokine and its re ceptor preferentially in the meninges and subarachnoid space in both hydroc ephalic and control mice. Reverse transcriptase-PCR analysis demonstrated t issue-specific expression of the TGF beta(1) gene in the brains of transgen ic mice, and enzyme-linked immunosorbent assay confirmed overexpression of the TGF beta(1) cytokine in brain, cerebrospinal fluid, and plasma. Conclusions. The transgenic murine model provides a reproducible representa tion of congenital hydrocephalus. The authors hypothesize that overexpressi on of TGF beta(1) in the CNS causes hydrocephalus by altering the environme nt of the extracellular matrix and interfering with the circulation of cere brospinal fluid. A model of hydrocephalus in which the genetic basis is kno wn should be useful for evaluating hypotheses regarding the pathogenesis of this disorder and should also help in the search for new treatment strateg ies.