Type 1 insulin-like growth factor receptor signaling is essential for the development of the hippocampal formation and dentate gyrus.
Type 1 insulin-like growth factor receptor (IGF1R) signaling in neuronal development was studied in mutant mice with blunted igf1r gene expression in nestin-expressing neuronal precursors. At birth [postnatal (P) day 0] brain weights were reduced to 37% and 56% of controls in mice homozygous (nes-igf1r(-/-)) and heterozygous (nes-igf1r(-/Wt)) for the null mutation, respectively, and this brain growth retardation persisted postnatally. Stereological analysis demonstrated that the volumes of the hippocampal formation, CA fields 1-3, dentate gyrus (DG), and DG granule cell layer (GCL) were decreased by 44-54% at P0 and further by 65-69% at P90 in nes-igf1r(-/Wt) mice. In nes-igf1r(-/-) mice, volumes were 29-31% of controls at P0 and, in the two mice that survived to P90, 6-19% of controls, although the hilus could not be identified. Neuron density did not differ among the mice at any age studied; therefore, decreased volumes were due to reduced cell number. In postnatal nes-igf1r(-/Wt) mice, the percentage of apoptotic cells, as judged by activated caspase-3 immunostaining, was increased by 3.5-5.3-fold. The total number of proliferating DG progenitors (labeled by BrdU incorporation and Ki67 staining) was reduced by approximately 50%, but the percentage of these cells was similar to the percentages in littermate controls. These findings suggest that 1) the postnatal reduction in DG size is due predominantly to cell death, pointing to the importance of the IGF1R in regulating postnatal apoptosis, 2) surviving DG progenitors remain capable of proliferation despite reduced IGF1R expression, and 3) IGF1R signaling is necessary for normal embryonic brain development.
Department of Pediatrics, Division of Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Wen
W
Liu
Ping
P
Ye
John R
JR
O'Kusky
A Joseph
AJ
D'Ercole
D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D002540:Cerebral Cortex / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005804:Genes, Lethal; D017930:Genes, Reporter; D005838:Genotype; D006624:Hippocampus / Q000196:embryology / Q000254:growth & development* / Q000473:pathology; D007031:Hypothalamus / Q000196:embryology / Q000254:growth & development; D007381:Intermediate Filament Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D019076:Transgenes
D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D017526:Receptor, IGF Type 1