Molecular studies of postnatal striatal development.

摘要

Transforming growth factor alpha (TGF-{dollar}alpha{dollar}) is a mitogenic factor and a neurotrophic factor which binds to the epidermal growth factor receptor (EGF-R). Using a ribonuclease protection assay, we found that TGF-{dollar}alpha{dollar} steady state mRNA levels in the mouse striatum peak during the first week of postnatal life. Bromodeoxyuridine (BrdU) labeling combined with immunohistochemistry of normal P6 brain showed that proliferating cells in the subependymal layer (SEL) are EGF-R immunoreactive. EGF-R immunoreactive cells were also localized to the SEL of the adult mouse forebrain. We measured glial fibrillary acidic protein (GFAP) mRNA levels in the striatum and observed that the peak of GFAP expression followed that of TGF-{dollar}alpha{dollar} by one week. In a TGF-{dollar}alpha{dollar} deficient mouse, waved-1, a significant reduction of GFAP mRNA levels and immunostaining for GFAP was found in the striatum. In the waved-1 SEL, there were fewer BrdU positive cells and there was a reduced level of {dollar}sp3{dollar}H-thymidine incorporation in the mutant striatum. Our data suggest that the TGF-{dollar}alpha{dollar}/EGF-R signaling pathway is involved in postnatal mitogenic events in the brain.; We detected a significant decline in striatal TGF-{dollar}alpha{dollar} mRNA which correlated temporally with known regional reductions in dopamine concentrations during nigrostriatal degeneration in the weaver mutant mouse. We also found significant decreases in TGF-{dollar}alpha{dollar} mRNA in the weaver hippocampus, but not in the weaver olfactory tubercle. Using an RIA to measure total T4, we determined that the weaver mouse has significantly reduced serum thyroid hormone levels postnatally. We found significantly reduced TGF-{dollar}alpha{dollar} steady state mRNA levels under experimentally induced hypothyroidism in the dorsal striatum and olfactory tubercle, but not in the hippocampus. In the weaver brain, we found significant reductions in striatal NGF mRNA levels in the striatum specifically at P18, which were reversible when postnatal thyroid hormone injections were administered to the mutants. Striatal Choline Acetyl Transferase (ChAT) activity, which is normally reduced by hypothyroidism, is not reduced in the weaver mouse. We conclude reduced serum thyroid hormone levels may contribute to the some aspects of the weaver phenotype.