Blunting type 1 insulin-like growth factor receptor expression exacerbates neuronal apoptosis following hypoxic/ischemic injury
© Liu et al; licensee BioMed Central Ltd. 2011
Received: 11 May 2011
Accepted: 30 June 2011
Published: 30 June 2011
Abundant experimental data have implicated an important role for insulin-like growth factor (IGF) in protecting neuronal cells from injury, including hypoxia/ischemia (H/I) injury, a major cause of neuron death. While the specific interaction of IGFs with neuronal or glial type 1 IGF receptors (IGF1R) has been shown to be essential to IGF actions during development, the same has not been directly demonstrated following H/I injury. To directly examine the role of neuronal IGF1R following H/I injury, we utilized conditional mutant nes-igf1r -/Wt mice and determined the impact of IGF1R haplodeficiency specifically in nestin-expressing neuronal precursors and their progeny on H/I-induced neuronal damage and apoptosis in hippocampus.
H/I induced significant damage to the cerebral hemisphere and hippocampus ipsilateral to the ligated right common carotid artery both in control and nes-igf1r -/Wt mice at postnatal day 10. Blunting IGF1R expression, however, markedly exacerbated H/I-induced damage and appeared to increase mortality. In the ipsilateral hemisphere and hippocampus, nes-igf1r -/Wt mice had infarct areas double the size of those in controls. The size of the ipsilateral hemisphere and hippocampus in nes-igf1r -/Wt mice were 15% to 17% larger than those in controls, reflecting more severe edema. Consistent with its effects on infarct area, IGF1R haplodeficiency causes a greater decrease in neurons in the ipsilateral hippocampus of nes-igf1r -/Wt mice. The reduction in neurons was largely due to increases in neuronal apoptosis. Judged by pyknotic nuclei, TUNEL and caspase-3 labeling, nes-igf1r -/Wt mice had significantly more apoptotic cells than that in controls after injury. To determine possible mechanisms of IGF1R actions, the mRNA expression of the pro-survival proteins IAP-1 and XIAP was determined. Compared to controls, the abundance of cIAP-1 and XIAP mRNA was markedly suppressed in mice with blunted IGF1R or IGF-I expression, while was increased in the brain of IGF-I overexpressing transgenic mice.
IGF1R in neuronal cells is critically important for their survival following H/I injury, and IGF-upregulated expression of neuronal cIAP-1 and XIAP likely in part contributes to IGF-IGF1R protection against neuronal apoptosis following H/I injury.
Hypoxia/ischemia (H/I) during prenatal brain development is a major cause of neural cell loss, and consequently morbidity and mortality in infants and children . It is estimated that 0.1% - 0.2% of full-term infants and ~50% of surviving preterm infants suffer brain damage caused by H/I injury , leading to cerebral palsy, epilepsy, cognitive deficits and growth retardation in affected children.
Several lines of experimental evidence implicate insulin-like growth factor (IGF) in protecting neurons from injury-induced cell death and in promoting neural repair during recovery: 1) IGF-I mRNA abundance falls sharply in injured and surrounding areas during the first 24 hr following H/I injury [3–5], concurrent with significant neuronal apoptosis during this time ; and then increases during recovery [4, 5]. 2) Injection of exogenous IGF-I into the lateral ventricle immediately or shortly after H/I injury attenuates H/I-induced brain damage and neuron loss [7–9], and oligodendrocyte precursor damage . Locally administered IGF-I also promotes neural tissue recovery [8, 9, 11]. 3) More recently, peripherally administered IGF-I (through subcutaneous injection  or nasal insufflation ) mitigates H/I brain injury significantly, in part by promoting the survival of neuronal cells and the proliferation of neural precursor cells. Notably, IGF-I remains effective when given by subcutaneous injection 24 and 48 hrs after H/I injury , a finding that supports its potential clinical utility in treating ischemic neural injury.
The type 1 IGF receptor (IGF1R) is essential in mediating IGF actions during neural cell development [14–16]. Whether the IGF1R also plays a key role in IGF's neuroprotection and/or promotion of neural regeneration following H/I injury, however, has not been directly demonstrated. In an earlier study, the data of Guan et al  raised the possibility that these IGF-I actions involve mechanisms in addition to those mediated by the IGF1R. des-IGF-I, an IGF-I analog lacking the N-terminal three peptides, retains the high affinity of the native peptide for the IGF1R, but has greatly reduced affinity for IGF binding proteins (IGFBPs). Consequently, it is generally more potent than native IGF-I, because its actions are not inhibited by IGFBPs. Nonetheless, Guan et al.  showed that des-IGF-I was much less effective than native IGF-I in mitigating H/I-induced brain damage, suggesting that IGF-I could exert its effects independent of IGF1R and/or that it requires IGFBPs.
To directly address the role of the IGF1R in neuroprotection following H/I, we studied neuronal cell survival following H/I in conditional mutant mice in which the IGFIR expression is halved specifically in nestin-expressing neuronal precursors and their progeny (nes-igf1r -/Wt ). We demonstrated that signaling through IGF1R is critically important for neuronal cell survival in developing brains following H/I injury.
The number of mice that die during hypoxia/ischemia (H/I) and within 48 hr following H/I insult.
Number of Mice That Died
Within 48 hours following H/I
Blunting neuronal IGF1R expression increases H/I-induced brain edema
Volume of hippocampus in nes-igf1r -/ W t and control mice at 1 DAI (mm3, mean ± SE).
18.59 ± 0.50
19.64 ± 0.47
13.67 ± 0.37
16.71 ± 0.93*
2.29 ± 0.21
2.67 ± 0.26#
1.04 ± 0.52
1.41 ± 0.11**
Blunting neuronal IGF1R expression exacerbates H/I-induced infarct
Blunting neuronal IGF1R expression exacerbates H/I-induced reduction of HIP and DG neurons
To more precisely define the impact of reduced IGF1R expression on neuronal cells following H/I injury, we performed stereological analysis of HIP and DG. HIP and DG have a distinct and relatively simple cyto-architecture that facilitates our analysis of neuronal cell response following injury.
Blunting IGF1R expression in nes-igf1r -/Wt mice resulted in a more dramatic reduction in the density of neurons in both H/I-injured ipsilateral CA PCL and DG GCL. When compared to control mice at 1 DAI, nes-igf1r -/Wt mice exhibited a trend toward a reduction in relative neuron density in ipsilateral CA3 PCL and GCL (by 15%), and in CA1 and CA2 PCL (by 30-34%). At 3 DAI the relative density of neurons was significantly reduced by 45 - 50% in PCL of CA regions and in GCL of DG (Figure 4). At 7 DAI the relative densities of ipsilateral CA and DG neurons in nes-igf1r -/Wt mice remained reduced in CA1.
Blunting neuronal IGF1R expression aggravates H/I-induced apoptosis in HIP and DG neurons
Injury-induced cell death largely contributed to the neuronal loss observed in both nes-igf1r -/Wt and control mice. When the histological appearance of pyknosis was used as a measure, more than 90% of the damaged cells appeared to be apoptotic during the course of the experiment. Few neurons in HIP and DG contralateral to the ligated right common carotid artery underwent apoptosis, and the density of pyknotic cells was from 20 - 114 cells/mm2 in control mice and 57 - 361 cells/mm2 in nes-igf1r -/Wt mice, respectively. When compared to control mice during development, the density of pyknotic cells was significantly increased in nes-igf1r -/Wt mice, a finding that is consistent with our previous report . A marked increase in the number of pyknotic cells in nes-igf1r -/Wt mice also was observed when pyknotic cells number was expressed as a percent of total cell number (0.37% - 1.76% in control mice and 2.37% - 7.69% in nes-igf1r -/Wt mice).
IGF-I-IGF1R signaling promotes survival protein mRNA expression
Our data strongly indicate that the interaction of IGF and IGF1R in neuronal cells plays an important role in neuronal survival against H/I brain injury. We found that nes-igf1r -/Wt mice with blunted IGF1R expression specifically in nestin-expressing neuronal precursors and their progeny exhibit exacerbated H/I-induced injury. Specifically, compared to normal mice these mutant mice have: 1) worsened brain edema, 2) increased rates in neuronal death, leading to greater decreases in neuron number, and 3) increased infarct area. We also show that a reduction in signaling through IGF1R significantly down-regulates the mRNA expression of cIAP-1 and XIAP, two IAP family proteins that are capable of suppressing cell apoptosis in multiple cell types, including neurons. In contrast, overexpression of IGF-I in brain increases the mRNA expression of cIAP-1 and XIAP. These data suggest that the down-regulated expression of neuronal cIAP-1 and XIAP, caused by reduction in neuronal IGF-IGF1R signaling, contributes to the aggravated neuronal apoptosis and H/I brain injury in nes-igf1r -/Wt mice.
H/I brain injury causes significant brain edema in rats that begins 30 minutes after injury and remains 6 DAI . Consistently, our results show that the ipsilateral ischemic hemispheres and hippocampuses had much larger volumes than the contralateral control hemispheres and hippocampuses, and these acute increases in volume must result from edema. Furthermore, when IGF1R expression was halved in nes-igf1r -/Wt mice, the relative increases in ipsilateral hippocampal volume induced by H/I injury were much larger, and likely represented increases in the severity of edema. This finding further supports an important role for IGF-IGF1R signaling in protecting brain from H/I-induced injury. Because the Crenestin transgene is not expressed in brain blood vessels (our unpublished data) and brain vascular IGF1R signaling and cytoarchitecture is apparently normal in nes-igf1r -/Wt mice , the aggravated brain edema in H/I-injured nes-igf1r -/Wt mice is likely a result of increased responses to more severe neuronal damage. A possible compromise of blood brain barrier secondary to neuronal injury, however, cannot be excluded.
Cell death in injured areas is a hallmark of the H/I-induced brain damage, and usually begins shortly after H/I and continues for several days, reaching its peak 2 - 3 DAI [24, 25]. In line with previous reports, we also observed abundant loss of neuronal cells during the first 3 days after injury. Most of the observed dying/dead neuronal cells exhibited characteristics of programmed cell death (i.e., apoptosis), such as condensed nuclei, nuclear DNA fragmentation that can be end labeled, and an increased abundance of active caspase-3. Our data, thus, are consistent with published data [22, 24–26], and indicate that under our experimental conditions the majority of dead neuronal cells underwent apoptosis, although necrosis also is likely to contribute to H/I-induced cell death. When compared to control mice, blunting IGF1R expression in nes-igf1r -/Wt mice resulted in 6 - 11 fold more dead cells during the first 3 days after injury. At 7 DAI the number of dead cells observed was still increased but more modestly (by 2 - 3 fold). These results indicate that biallelic IGF1R expression is required for the normal survival of hippocampal neurons after H/I-induced injury, and that IGF1R signaling may be more critical in neuronal survival during the first 3 days after injury.
It is well-documented that the expression of both IGF-I and IGF-II, IGF1R ligands, is temporally and spatially regulated in H/I-injured brain (see reviews by D'Ercole et al.  and Popken et al. ). Alteration in serum IGFs in subjects with H/I brain injury also has been reported [29, 30]. While IGF-I has been widely implicated in neuronal protection and repair following H/I, the functions of IGF-II in H/I brain injury is not clear. Guan and co-workers  have shown that administering IGF-II does not reduce cortical infarction induced by H/I, and that co-administration of IGF-II with IGF-I abolishes the protective effects of IGF-I. These data suggest that IGF-II likely has a function(s) that differs from IGF-I. Under our experimental conditions it is not clear whether the IGF1R exerts its neuroprotective effects by interacting with IGF-I, IGF-II or both. Regardless of its ligand, or the origin of these ligands, our data strongly indicate an important role for signaling through IGF1R in neuronal protection following H/I injury.
cIAP-1 and XIAP, two members of IAP family proteins, are capable of suppressing the activity of caspases (the enzymes that are involved in apoptotic destructive processes) by either enhancing caspase degradation (cIAP) or directly inhibiting their activity (XIAP) . The findings that cIAP-1 and XIAP mRNA is increased in IGF-I overexpressing transgenic mice and markedly reduced in nes-igf1r -/Wt mice and IGF-I null mutant mice demonstrate that signaling through IGF1R has an important role in regulating the expression of mRNA for these two proteins during brain development. We further showed that following injury the expression of cIAP-1 and XIAP mRNA is increased in ipsilateral hemisphere, and that these increases are dampened by IGF1R haploinsufficiency. These data suggest that increased cIAP-1 and XIAP, at least in part, mediates the anti-apoptotic effects of IGF signaling in CNS neuronal cells during development and following H/I injury.
Taken together, our data demonstrated that blunting IGF1R expression specifically in neuronal cells exacerbates H/I-induced injury, and thus, are consistent with the proposition that IGF-IGF1R interaction in neuronal cells is critically important for their survival following H/I injury. In addition, our data showing that IGF-IGF1R signaling up-regulates the expression of neuronal cIAP-1 and XIAP during development and following H/I, strongly suggest that cIAP-1 and XIAP are two candidate targets for therapeutic treatment of H/I-induced brain injuries.
Animals and H/I Injury
Nes-igf1r -/Wt conditional mutant mice, generated as previously described , were bred as heterozygotes. As previously reported, igf1r lox/Wt and nestin-Cre transgenic mice have normal postnatal growth, and our preliminary studies show that these mice exhibit similar changes to those of wildtype (Wt) mice in responding to H/I injury. Thus, these mutant mice were grouped and considered controls. Transgenic mice that express a human IGF-I cDNA driven by a metallothionein-I promoter (IGF-I transgenic mice) , and mice with a global IGF-I null mutation (igf-I -/- [14, 33] also have been described elsewhere. All procedures used were consistent with the guidelines of the National Institutes of Health and approved by the institutional review committees of the University of North Carolina at Chapel Hill.
H/I injury was done using a modified method [34, 35] that was adapted from a neonatal rat method . Briefly, mice at postnatal day 10 (weighting 4 to 5 grams) were subjected to artery ligation surgery or sham surgery under isoflurane anesthesia (4% for induction and 1.5-2% for maintenance). After the skin was sterilized with 75% ethanol and 10% povidone-iodine, a midline neck incision (0.5 - 1 cm in length) was made, and the right common carotid artery was carefully isolated and ligated with a bipolar coagulator. The wound was then closed with interrupted nylon sutures. During the procedure, which typically took no longer than 10 minutes, body temperature was maintained using a heating lamp. After ligation or sham surgery, mice were allowed to recover from anesthesia in a chamber partially submerged in a 37°C water bath. After ~10 minutes, mice were returned to their dam. One hour after surgery, mice were individually placed in a chamber that was partially submerged in a water bath (36 ± 0.2°C), subjected to hypoxia (10% O2, balanced with N2) for 45 minutes, and then were returned to their dam. Both control mice and nes-igf1r -/Wt mice resumed normal activity and feeding within 5-10 minutes after return to their dam.
Mice were sacrificed 1, 3 or 7 DAI. Similar to previously reported data [18, 36], control mice or nes-igf1r -/Wt mice, which underwent hypoxia alone, ischemia alone, sham surgery, or sham surgery followed by hypoxia, exhibited similar body growth, behavioral and brain morphological characteristics as their intact untreated counterparts. H/I injury resulted in a suboptimal somatic growth (see Results and Figure 1). As we previously reported, reduction in IGF1R expression causes brain growth retardation , and therefore, all changes are expressed as% of the contralateral brain hemisphere, except where indicated.
Histology and Stereological Analysis
After being fixed by submersion in 4% paraformaldehyde overnight, brains were paraffin-embedded, and coronally sectioned at 8 μm in thickness. Two to three sets of serial sections that comprised very 10th section were collected. To estimate the volume of brain regions, one series of sections were stained with cresyl violet, and the area of brain regions on each section (corresponding to plates between number 41 and 52 ) was measured under a microscope, assisted with Stereo Investigator software (Microbrightfield, Colchester, VT). The volume (V) was then estimated using the formula: V = ΣA × T × I, where ΣA = sum of area measured on each section, T = section thickness, and I = section intervals.
To determine the density of pyramidal neurons in CA PCL regions and granule neurons in DG GCL, stained section corresponding to plate 50  from each brain was selected, and cell nuclei within delineated areas were counted, assisted with Stereo Investigator software. In each section the cell density in each brain region was calculated by dividing the regional cell count by its respective area.
To determine infarct area, sections corresponding to plate 50  from each paraffin-embedded brain were stained with cresyl violet. The area of infarct in the ipsilateral hemisphere was then measured using Stereo Investigator, as described above.
To evaluate possible brain swelling/edema after H/I injury, some brains were fresh-frozen in liquid N2 to preserve water content and brain structures. Serial sections (20 μm in thickness) were cut coronally on a cryostat. Two to three sets of serial sections that comprised every 6th section were collected. One series of sections (also corresponding to plates between number 41 and 52) were fixed with 4% paraformaldehyde, and stained with cresyl violet. The areas of ipsilateral and contralateral hemisphere and hippocampus were measured, and their volumes were calculated as described above.
Terminal uridine nucleotide end labeling (TUNEL)
After paraffin-sections (corresponding to plate ) were dewaxed and rehydrated, TUNEL-positive apoptotic cells were detected using an In Situ Cell Death Detection Kit (Roche Applied Science, Indianapolis, IN), following the manufacturer's protocol. The sections were then counterstained with the nuclear dye 6-diamidine-2'-phenylindole dihydrochloride (DAPI, Invitrogen, Carlsbad, CA). Images of TUNEL-positive cells within CA and DG regions were digitally captured using a microscope and a Spot Jr. digital camera (Diagnostic Instruments, Sterling Heights, MI). Within delineated areas (measured and assisted with a Stereo Investigator software), TUNEL-positive cells were counted, and then their densities were calculated.
Quantitative Real Time-PCR (qRT-PCR) and Northern Blot Hybridization Analysis
Slides containing coronal frozen-sections (20 μm in thickness, and corresponding to plate 48 - 50) were briefly air-dried. Contralateral and ipsilateral hemisphere tissues were scraped from the slides and collected, and total RNA was isolated using a RNA plus kit (Qiagen, Valencia, CA). cDNA reverse transcription was performed, and the resultant mRNA-derived cDNA was quantified by qRT-PCR using specific primer sets. The sequences of the primers used are as follows: cIAP-1 (Genbank accession number: BC145985), forward primer: 5'-gatggtggcttgagatgttgg-3', reverse primer, 5'-tttctccagggccaaaatgc-3'; XIAP (Genbank accession number: NM_009688), forward primer, 5'-ctattggatgagaaggggcaag-3', reverse primer, 5'-atagatagctgctcccggatg-3'. Primers for 18S rRNA were obtained from Invitrogen. The abundance of mRNA was determined, based on a standard curve for each target mRNA and 18S rRNA, as described .
Northern blot hybridization and quantification of mRNA abundance on blots were performed as previously described . Total RNA was isolated using the acidic guanidinium thiocyanate-phenol-chloroform method . 32P-labeled single stranded cDNA probes were generated as previously described , using plasmid containing XIAP (also known as MIHA) or cIAP-1 (also known as BIRC2 or MIHB) cDNA. XIAP and cIAP-1 plasmids were generously provided by Dr. Uren . PCR-amplified XIAP and cIAP-1 cDNA fragments correspond to base pairs (bp) 584-870 (Genbank accession number: U36842) and bp 1685-1898 (Genbank accession number: U37547), respectively.
All experiments were repeated at least two times. Student-t test or one-way ANOVA was used to test statistical significance among the groups, followed by comparison of each group mean with the Newman-Keuls-Student test assisted with the software SigmaStat for Windows (SPSS, Inc., Chicago, IL).
This work was supported by NIH grants RO1 HD008299 and RO1 NS48868. The authors wish to thank Dr. William Lagard for his help in the setup of H/I instruments.
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