Systems genetic analysis of the effects of iron deficiency in mouse brain
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Iron regulation in the brain is both necessary and highly complex. Too little or too much iron can compromise neurological function, yet we still do not know all of the regulatory processes. In our research, we seek to identify genes and gene networks underlying individual differences in brain iron regulation. To this end, we fed mice from 20+ inbred strains a diet low in iron from weaning to 4 months of age. At sacrifice, we measured iron content in the ventral midbrain (VMB). The VMB contains the substantia nigra, a region particularly vulnerable to iron imbalance. The results showed high, inter-strain variability in dietary iron reduction, from almost no loss to more than 40 % vs. control. When we performed quantitative trait loci (QTL) analysis, we observed a significant area on chromosome 2. Within this QTL, we selected glial high-affinity glutamate transporter 1 (Glt1) as the leading candidate. Expression of this gene is both correlated with VMB iron and is also cis-modulated by local sequence variants that segregate in the BXD family. VMB expression differences of Glt1 in six strains covary with differential susceptibility to VMB iron loss.
KeywordsBXD Ventral midbrain Recombinant inbred Quantitative trait loci Glial glutamate high-affinity transporter
This work was funded in part by NIA Grant # PO1AG021190, by a grant from the Restless Legs Foundation, by NRSA fellowship 5F31NS060393 to LCJ, and by NIAAA grants U01AA016662 and U01AA016667 to MFM and U01AA13499 to LL and RWW. The authors thank Dr. Kennie Jones for his contributions to database management and Dr. Lisa Tarantino for assistance with identifying polymorphisms within Glt1.
Conflict of interest
The authors declare no conflicts of interest in this research.
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