Impaired brain development and hydrocephalus in a line of transgenic mice with liver-specific expression of human insulin-like growth factor binding protein-1

Insulin-like growth factors (IGFs) produced in the brain are known to parti cipate in brain development via activation of the type 1 IGF receptor. IGF binding proteins (IGFBPs) modulate the cellular action of IGFs and some are expressed in the fetal brain. Under normal conditions IGFBP-1 is not one o f these, but IGFBP-1 expression obtained via transgenesis using ubiquitous promoters affects brain development. In earlier work, we established a mode l of transgenic mouse in which liver-specific IGFBP-1 expression begins dur ing fetal life. The repercussions of this IGFBP-1 over-expression include r eproductive defects, ante- and perinatal mortality and post-natal growth re tardation, the extent of which is related to the degree of transgene expres sion. Unexpectedly, during the first 2 months of postnatal life, there were some cases of head enlargement revealing hydrocephalus among homozygotes, frequently associated with motor disorders. Brain sections showed dilatatio n of the lateral ventricles in 10 out of 15 homozygotes examined. Histologi cally, dilatation was evident in four out of nine heterozygotes. Brain weig ht in transgenics was relatively less reduced than the weights of other org ans. Hence, brain weight/body weight ratios were normal in heterozygotes an d on average higher than normal in homozygotes. The width of the cerebral c ortex was reduced in homozygotes, with disorganized neuronal layers. The co rpus callosum was underdeveloped, particularly in homozygotes. The area of the hippocampus was reduced in homozygotes and one-third of the heterozygot es, with a short and thick dentate gyrus in the former. Similar anomalies h ave been reported in mice with disruption of the igf-l gene and in a model of transgenic mice over-expressing IGFBP-1 in all tissues, including the br ain. Hydrocephalus was not mentioned in these reports, raising the possibil ity that insertional mutagenesis may have been involved in our mice. Nevert heless, our observations indicate that hepatic over-expression of IGFBP-1 m ay have endocrine effects on brain development. (C) 2000 Harcourt Publisher s Ltd.