Astrocyte-specific overexpression of insulin-like growth factor-I promotes brain overgrowth and glial fibrillary acidic protein expression.
Insulin-like growth factor-I (IGF-I) is widely expressed in the central nervous system (CNS). Whereas during normal development IGF-I is expressed predominantly by neurons and to a much lesser degree by glial cells, its expression in astrocytes, and often in microglia, is increased during and/or after variety of CNS injuries. Recently we have generated a new line of IGF-I Tg mice, called IGF-I(Ast/Tet-Off) Tg mice, in which IGF-I transgene is expressed specifically in astrocytes and is tightly controlled by the tetracycline analog doxycycline. In this study we examined whether IGF-I derived from astrocytes is capable of promoting neural cell growth during development. When the IGF-I transgene is allowed to be expressed, IGF-I(Ast/Tet-Off) Tg mice exhibit markedly increases in 1) brain weight; 2) brain DNA and protein abundance; and 3) number of neurons, oligodendrocytes, and astrocytes, as well as myelination, findings similar to those observed in our other lines of Tg mice that express IGF-I transgene predominantly in neurons. Unlike Tg mice with neuron-specific IGF-I expression, which manifest marked increases in the concentrations of oligodendrocyte/myelin-specific proteins, however, IGF-I(Ast/Tet-Off) Tg mice exhibit an increase in the concentration of glial fibrillary acidic protein, an astrocyte-specific protein. Furthermore, when transgene expression is blunted, brain overgrowth in IGF-I(Ast/Tet-Off) Tg mice ceases. Our data indicate that astrocyte-derived IGF-I is capable of promoting neural cells growth in vivo. Our data also suggest that IGF-I's actions in CNS depend in part on the location of its expression and cellular microenvironment and that continuous presence of IGF-I expression is necessary for brain overgrowth.
Ye
Ping
P
Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ping_ye@med.unc.edu
Popken
Greg J
GJ
Kemper
April
A
McCarthy
Ken
K
Popko
Brian
B
D'Ercole
A Joseph
AJ
D000367:Age Factors; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001835:Body Weight; D001921:Brain / Q000033:anatomy & histology / Q000166:cytology* / Q000254:growth & development; D002452:Cell Count / Q000379:methods; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D009929:Organ Size / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014746:Vimentin / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D014746:Vimentin; D007334:Insulin-Like Growth Factor I; D004318:Doxycycline