Open AccessTargeted Gene Expression Analysis in Hemimegalencephaly: Activation of β‐Catenin Signaling
Author(s) -
Yu Jia,
Baybis Marianna,
Lee Allana,
McKhann Guy,
Chugani Diane,
Kupsky William J.,
Aronica Eleonora,
Crino Peter B.
Publication year - 2005
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/j.1750-3639.2005.tb00518.x
Subject(s) - wnt signaling pathway , cyclin d1 , biology , creb , transcription factor , gene expression , cancer research , signal transduction , growth factor , gene , transforming growth factor , microbiology and biotechnology , cell cycle , genetics , receptor
Hemimegalencephaly (HMEG) is a developmental brain malformation characterized by unilateral hemispheric enlargement, cytoarchitectural abnormalities, and an association with epilepsy. To define the developmental pathogenesis of HMEG, the expression of 200 cell signaling, growth, angiogenic, and transcription factor genes was assayed in HMEG samples (n = 8) with targeted cDNA arrays. Differential expression of 31 mRNAs across the 4 gene families was identified in HMEG compared with control cortex. Increases in growth and transcription factor genes included JNK‐1, cyclic AMP response element binding protein (CREB), and tuberin mRNAs and decreases included insulin‐like growth factor‐1 (IGF‐1), transforming growth factor β‐3 (TGF‐β3), and NF k B mRNAs. Increased expression of cyclin D1, c‐myc, and WISP‐1 mRNAs in HMEG suggested activation of the Wnt‐1/β‐catenin cascade. Western analysis demonstrated increased levels of non‐phosphorylated β‐catenin, which transcriptionally activates cyclin D1 and c‐myc genes, but reduced levels of Ser33/Ser37/Thr41 phospho‐β‐catenin, which is essential for β‐catenin‐inactivation, in HMEG. Altered expression of 31 mRNAs from 4 gene families in human HMEG may lead to aberrant cell growth and hemispheric enlargement during brain development. Enhanced cyclin D1 and c‐myc transcription likely reflects increased transcriptionally active β‐catenin due to decreased Ser33/Ser37/Thr41 phospho‐β‐catenin and suggests activation of the Wnt‐1/β‐catenin cascade in HMEG.