[Abstract Title]. - Society for Neuroscience

Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 229.6/A6
Topic: A.02.a. Proliferation
Support: NIH Grant RO1HD008299
Title: The effect of the type 1 insulin-like growth factor receptor signaling on neurogenesis in
the postnatal development of the dentate gyrus
Authors: *W. LIU, P. YE, A. J. D'ERCOLE;
Dept Pediatric, Univ. North Carolina-Chapel Hill, Chapel Hill, NC
Abstract: It has been shown that Insulin-like growth factor-I (IGF-I) is essential to normal brain
growth and development, and that most of its actions are mediated by the type 1 IGF receptor
(IGF1R). To directly assess the in vivo effects of IGF-I-IGF1R signaling on neurogenesis, we
have generated mutant mice with blunted IGF1R expression specifically in neuronal precursors.
In these mutant mice, termed nes-igf1r -/Wt mice, the function of one igf1r allele is ablated by
Cre-mediated deletion of exon 3 of the igf1r gene directed by nestin genomic regulatory
elements. Previously we found that in the dentate gyrus of nes-igf1r -/Wt mice the volume of
granule cell layer and the number of granule neurons were significantly reduced at postnatal day
(P) 5 and P20. To further define the actions of IGF-I-IGF1R signaling during postnatal
development of dentate gyrus, proliferation, survival, and developmental progression of neuron
precursors were determined. As judged by immunostaining for Ki67, a cell cycle marker,
proliferating cells in subgranule layer were reduced by 65% in nes-igf1r -/Wt mice at P20, as
compared to their littermate controls. Consistently, following a single injection of BrdU 3 hr
prior to tissue collection, the number of dividing cells in S-phase was reduced by 60% in P20
nes-igf1r -/Wt mice. In contrast, the density of apoptotic cells, assessed by immunostaining for
active caspase 3, was increased by 78% in the granule cell layer of P20 nes-igf1r -/Wt mice. The
progression of neuron precursors was then determined by evaluating the number of cells that
express transcription factors characteristic of early progenitors (Pax6), intermediate progenitor
cells (Tbr2), and granule neurons (Tbr1). Compared to controls, P5 nes-igf1r -/Wt mice exhibited a
significant decrease in the number of Pax6 positive cells (by 40%), Tbr2 positive cells (by 55%)
and Tbr1 positive cells (51%). Similarly, the number of Pax6, Tbr2 and Tbr1 positive cells was
reduced by 74%, 63% and 74%, respectively, in P20 nes-igf1r -/Wt mice. These results strongly
indicate that IGF-I-IGF1R signaling plays a critical role in dentate gyrus neurogenesis by
stimulating proliferation and by augmenting survival of neuron lineage cells.
Disclosures: W. Liu , None; P. Ye, None; A.J. D'Ercole, None.
Poster