| Transforming growth factor {dollar}beta 1{dollar} (TGF-{dollar}beta 1){dollar} is a member of a superfamily of cytokines that influence a variety of tissue remodeling events during embryogenesis, inflammation, and wound healing. The role of TGF-{dollar}beta 1{dollar} in the developing central nervous system (CNS) is suggested by in vitro studies of neuronal, glial, and leptomeningeal cells where TGF-{dollar}beta 1{dollar} promotes cell differentiation, modulates response to mitogens, and increases the extracellular matrix. Thus, the collective effect of TGF-{dollar}beta 1{dollar} may be to establish and stabilize CNS cell differentiation, suggesting an important in vivo regulatory role for TGF-{dollar}beta 1{dollar} in CNS development and response to injury.; Through transgenic techniques, we have investigated constitutive expression of activated TGF-{dollar}beta 1{dollar} in the CNS in vivo, by utilizing a promoter containing regulatory elements within the human glial fibrillary acidic protein gene linked to a modified TGF-{dollar}beta 1{dollar} cDNA. The majority of these mice (TgN4Mes) develop progressive communicating hydrocephalus associated with a failure of the lateral recesses of the fourth ventricle to open during late gestation, while in the few transgenic mice that remain asymptomatic, the outflow tracts form normally. The tela choroidea of hydrocephalic TgN4Mes fetuses has increased mesenchymal cell proliferation and TGF-{dollar}beta{dollar} type II receptor ({dollar}rm Tbeta R{dollar}-II) expression. Thus, the failure to develop open lateral recesses may, in part, result from excessive proliferation of leptomeningeal cells or extracellular matrix in the developing hindbrain. This CNS phenotype is similar to that observed following in utero exposure to a known regulator of TGF-{dollar}beta 1{dollar} expression, retinoic acid. In addition, the thickened leptomeninges are immunoreactive numerous extracellular matrix components, suggesting that TGF-{dollar}beta 1{dollar} release during CNS injury may factor into the pathogenesis of leptomeningeal fibrosis and secondary communicating hydrocephalus.; We have determined that overexpression of TGF-{dollar}beta 1{dollar} in the CNS of transgenic mice consistently results in hydrocephalus due to failed development of fourth ventricular lateral foramina, while concurrently increasing leptomeningeal proliferation and formation of subdural fibrosis. These findings suggest the potential for preventative benefit in the administration of anti-TGF-{dollar}beta 1{dollar} antibody or recombinant latency-associated peptide subsequent to CNS injury or hemorrhage. Finally, because TGF-{dollar}beta 1{dollar} crosses the placenta, prospective therapeutic strategies employing active TGF-{dollar}beta 1{dollar} should consider the possibility of complications in the fetus. |
