TY - JOUR
T1 - Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation
AU - Prabowo, Avanita S.
AU - Anink, Jasper J.
AU - Lammens, Martin
AU - Nellist, Mark
AU - van den Ouweland, Ans M. W.
AU - Adle-Biassette, Homa
AU - Sarnat, Harvey B.
AU - Flores-Sarnat, Laura
AU - Crino, Peter B.
AU - Aronica, Eleonora
PY - 2013
Y1 - 2013
N2 - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either the TSC1 or TSC2 genes and characterized by developmental brain abnormalities. We defined the spectrum of brain abnormalities in fetal TSC brain ranging from 23 to 38 gestational weeks. We hypothesized (i) prenatal activation of the target-of-rapamycin complex 1 (TORC1) signaling pathway; and (ii) activation of inflammatory pathways in fetal brain lesions. Immunocytochemical analysis of cortical tubers, as well as subependymal lesions in all cases confirmed the cell-associated activation of the TORC1 signaling pathway in both the cortical tubers and subependymal lesions (including a congenital subependymal giant cell astrocytoma) with expression of pS6, p4EBP1 and c-myc proteins, as well as of p70 S6 kinase 1. The lesions contained macrophages and T-lymphocytes; giant cells within the lesions expressed inflammatory response markers including major histocompatibility complex class I and II, Toll-like receptors (TLR) 2 and 4 and receptor for advanced glycation end products (RAGE). These observations indicate that brain malformations in TSC are likely a consequence of increased TORC1 activation during embryonic brain development. We also provide evidence supporting the possible immunogenicity of giant cells and the early activation of inflammatory pathways in TSC brain
AB - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either the TSC1 or TSC2 genes and characterized by developmental brain abnormalities. We defined the spectrum of brain abnormalities in fetal TSC brain ranging from 23 to 38 gestational weeks. We hypothesized (i) prenatal activation of the target-of-rapamycin complex 1 (TORC1) signaling pathway; and (ii) activation of inflammatory pathways in fetal brain lesions. Immunocytochemical analysis of cortical tubers, as well as subependymal lesions in all cases confirmed the cell-associated activation of the TORC1 signaling pathway in both the cortical tubers and subependymal lesions (including a congenital subependymal giant cell astrocytoma) with expression of pS6, p4EBP1 and c-myc proteins, as well as of p70 S6 kinase 1. The lesions contained macrophages and T-lymphocytes; giant cells within the lesions expressed inflammatory response markers including major histocompatibility complex class I and II, Toll-like receptors (TLR) 2 and 4 and receptor for advanced glycation end products (RAGE). These observations indicate that brain malformations in TSC are likely a consequence of increased TORC1 activation during embryonic brain development. We also provide evidence supporting the possible immunogenicity of giant cells and the early activation of inflammatory pathways in TSC brain
U2 - https://doi.org/10.1111/j.1750-3639.2012.00616.x
DO - https://doi.org/10.1111/j.1750-3639.2012.00616.x
M3 - Article
C2 - 22805177
SN - 1015-6305
VL - 23
SP - 45
EP - 59
JO - Brain pathology (Zurich, Switzerland)
JF - Brain pathology (Zurich, Switzerland)
IS - 1
ER -