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. 2016 Mar;31(4):426-32.
doi: 10.1177/0883073815596617. Epub 2015 Aug 3.

Dysregulation of FMRP/mTOR Signaling Cascade in Hypoxic-Ischemic Injury of Premature Human Brain

Mirna Lechpammer  1 , Pia Wintermark  2 , Katherine M Merry  3 , Michele C Jackson  3 , Lauren L Jantzie  4 , Frances E Jensen  5
Affiliations

Dysregulation of FMRP/mTOR Signaling Cascade in Hypoxic-Ischemic Injury of Premature Human Brain

Mirna Lechpammer et al. J Child Neurol. 2016 Mar.

Abstract

In this study the authors investigated whether dysregulation of the fragile X mental retardation protein and mammalian target of rapamycin signaling cascade can have a role in the pathogenesis of encephalopathy of prematurity following perinatal hypoxia-ischemia. The authors examined the brain tissue of newborns with encephalopathy and compared it to age-matched controls with normal brain development and adults. In normal controls, the fragile X mental retardation protein expression in cortical gray matter spiked 4-fold during 36-39 gestational weeks compared to the adult, with a concomitant suppression of p70S6K and S6. In encephalopathy cases, the developmental spike of fragile X mental retardation protein was not observed, and fragile X mental retardation protein levels remained significantly lower than in normal controls. Importantly, this fragile X mental retardation protein downregulation was followed by a significant overexpression of p70S6K and S6. These novel findings thus suggest that premature hypoxic-ischemic brain injury can affect the fragile X mental retardation protein/mammalian target of rapamycin pathway, as otherwise observed in inherited syndromes of cognitive disability and autism spectrum disorders.

Keywords: autism; brain injury; fragile X mental retardation protein; hypoxia; mammalian target of rapamycin; prematurity.

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Figures

Figure 1
Figure 1. FMRP expression in the brain during normal development and in encephalopathy of prematurity
A) Western blots quantification of total FMRP expression during normal human cortical development (n=15). Histograms represent averaged optical density normalized to actin, and expressed relative to the mean adult controls values (n=4). * p < 0.0001 vs. adult control, GW = gestational weeks; OD = optical density. Inset: representative western blot analyses for total and phospho-FMRP at five different developmental time points and in an adult control. B) Representative immunohistochemical stains showing overexpression of FMRP in the human cortex (brown staining) at 37 gestational weeks compared to 23 gestational weeks of normal development. White matter shows no difference in FMRP expression in the same gestational periods. C) Representative immunohistochemical stains showing no change in FMRP expression in the brain of patients with encephalopathy of prematurity during 23rd and 37th gestational weeks. D) FMRP/OLs (OLIG2) and FMRP/astrocytes (GFAP) double-labeling in white matter neurons showing no co-expression (Size bar 50 μm).
Figure 1
Figure 1. FMRP expression in the brain during normal development and in encephalopathy of prematurity
A) Western blots quantification of total FMRP expression during normal human cortical development (n=15). Histograms represent averaged optical density normalized to actin, and expressed relative to the mean adult controls values (n=4). * p < 0.0001 vs. adult control, GW = gestational weeks; OD = optical density. Inset: representative western blot analyses for total and phospho-FMRP at five different developmental time points and in an adult control. B) Representative immunohistochemical stains showing overexpression of FMRP in the human cortex (brown staining) at 37 gestational weeks compared to 23 gestational weeks of normal development. White matter shows no difference in FMRP expression in the same gestational periods. C) Representative immunohistochemical stains showing no change in FMRP expression in the brain of patients with encephalopathy of prematurity during 23rd and 37th gestational weeks. D) FMRP/OLs (OLIG2) and FMRP/astrocytes (GFAP) double-labeling in white matter neurons showing no co-expression (Size bar 50 μm).
Figure 2
Figure 2. Expression of components of the FMRP/mTOR signaling cascade in brain tissue of patients with encephalopathy of prematurity
Western blots quantification of A) FMRP and phospho-FMRP as well as B) mTOR downstream targets p70S6K and phospho-p70S6K during 37-38 gestational weeks in the cortex of patients with encephalopathy of prematurity (n=5) and in normal age-matched controls (n=6). Histograms represent averaged optical density normalized to actin. C) Representative Western blot analyses for total and phospho-p70S6K (n=4) and in an adult control. * p < 0.0001 vs. age-matched control, Ctrl. = control; EOP = encephalopathy of prematurity; GW = gestational weeks; OD = optical density.
Figure 3
Figure 3. phospho-S6 expression in the brain during normal development and in encephalopathy of prematurity
Representative immunohistochemical stain of phospho-S6 expression in human cortex and the white matter during normal brain development (no expression detected) and a positive staining in a newborn with encephalopathy of prematurity (EOP) during 37th gestational week. Insets: Examples of positive stain for phospho-S6 expression (600x) in a patient with encephalopathy of prematurity.
Figure 4
Figure 4
Representative immunohistochemical stains showing A) co-expression of mGluR5 and FMRP and B) mGluR5 and phospho-S6 (PS6) on the neurons of a newborn with encephalopathy of prematurity during 37th gestational week (600x; double staining with DAPI).
Figure 4
Figure 4
Representative immunohistochemical stains showing A) co-expression of mGluR5 and FMRP and B) mGluR5 and phospho-S6 (PS6) on the neurons of a newborn with encephalopathy of prematurity during 37th gestational week (600x; double staining with DAPI).
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