Characterization of a model of hydrocephalus in transgenic mice

Abstract

The purpose of this study was to elucidate the pathophysiology of hydrocephalus in a new transgenic model of mice created to overproduce the cytokine, transforming growth factor-ß1 (TGFß1), in the central nervous system (CNS). Galbreath and colleagues generated transgenic mice that overexpressed TGFß1 in the CNS in an effort to examine the role of this cytokine in the astrocytic response to injury. Unexpectedly, the animals developed severe hydrocephalus and died. The authors perpetuated this transgenic colony to serve as a model of congenital hydrocephalus, breeding asymptomatic carrier males that were heterozygous for the transgene with wild-type females. One hundred twelve (49.6%) of 226 mice developed clinical manifestations of hydrocephalus, which was characterized by dorsal doming of the calvaria, spasticity, limb tremors, ataxia, and ultimately death. The presence of the TGFß1 transgene was determined by performing polymerase chain reaction (PCR) analysis of sample cuts of tail. The 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 develope hydrocephalus. Alterations in brain structure were characterized using magnetic resonance (MR) imaging, gross and light microscopic analysis, and immunocytochemistry. Magnetic resonance imaging readily distinguished hydrocephalic animals from nonhydrocephalic controls, and it 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 TGFß1 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 TGFß1 gene in the brains of transgenic mice, and enzyme-linked immunosorbent assay confirmed the occurrence of overexpression of the TGFß1 cytokine in brain, cerebrospinal fluid, and plasma. The transgenic murine model provides a reproducible representation of congenital hydrocephalus. The authors hypothesize that overexpression of TGFß1 in the CNS causes hyrdocephalus 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 additionally, should help in the search for novel treatment strategies.