Deficient expression of insulin receptor substrate-1 (IRS-1) fails to block insulin-like growth factor-I (IGF-I) stimulation of brain growth and myelination.
To determine whether insulin receptor substrate-1 (IRS-1) is essential in mediating insulin-like growth factor-I (IGF-I) stimulation of brain growth and myelination in vivo, we cross-bred IGF-I transgenic (Tg) mice with IRS-1 null mutant (IRS-1(-/-)) mice and examined brain growth and expression of myelin-specific proteins in mice that overexpress IGF-I with or without IRS-1 expression. We found that while IGF-I overexpression stimulates a dramatic increase in brain weight (43%) by 7-8 weeks of age in the absence of IRS-1, it stimulates a greater increase (50%) with intact IRS-1 expression. To evaluate myelination we investigated IGF-I-stimulated expression of myelin basic protein (MBP) and proteolipid protein (PLP) in the cerebral cortex CTX and brainstem, and found similar increases in each region in IRS-1(-/-) and wild type mice. In studies using mixed glial cultures derived from IRS-1(-/-) mice, IGF-I also increased the abundance of MBP and PLP mRNA. To assess possible alternate mediators of IGF-I actions, we examined IRS-2 and IRS-4 and found that the abundance of each is increased in the CTX of IRS-1(-/-) mice and IGF-I Tg mice. Our results suggest that IRS-1 is not essential in IGF-I promotion of oligodendrocyte development and myelination, and that IRS-2 and IRS-4 may compensate for the loss of IRS-1 expression and function in the cells of oligodendrocyte lineage. Nonetheless, the finding that IGF-I stimulates brain growth less well in the absence of IRS-1 suggests that IRS-1-mediated signaling may be more central to IGF-I action in cells other than glia and oligodendrocytes.
Ye
Ping
P
Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Li
Liqin
L
Lund
P Kay
PK
D'Ercole
A Joseph
AJ
D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D009929:Organ Size / Q000235:genetics; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; C491531:Irs4 protein, mouse; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D010750:Phosphoproteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I