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

Brain Res Dev Brain Res. 2002 Jun 30;136(2):111-21. doi: 10.1016/s0165-3806(02)00355-3.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain / cytology
  • Brain / growth & development*
  • Brain / metabolism*
  • Cell Differentiation / genetics*
  • Female
  • Gene Expression Regulation, Developmental / physiology
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, Knockout
  • Myelin Basic Protein / genetics
  • Myelin Basic Protein / metabolism
  • Myelin Proteins / genetics
  • Myelin Proteins / metabolism*
  • Myelin Proteolipid Protein / genetics
  • Myelin Proteolipid Protein / metabolism
  • Myelin Sheath / genetics
  • Myelin Sheath / metabolism
  • Nerve Fibers, Myelinated / metabolism*
  • Oligodendroglia / metabolism*
  • Organ Size / genetics
  • Phosphoproteins / deficiency*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • RNA, Messenger / metabolism
  • Up-Regulation / genetics


  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • Irs2 protein, mouse
  • Irs4 protein, mouse
  • Myelin Basic Protein
  • Myelin Proteins
  • Myelin Proteolipid Protein
  • Phosphoproteins
  • RNA, Messenger
  • Insulin-Like Growth Factor I