title: Co-expression of cyclin D1 and phosphorylated ribosomal S6 proteins in hemimegalencephaly.
abstract: Hemimegalencephaly (HMEG) is a developmental brain malformation highly associated with epilepsy. Balloon cells (BCs) and cytomegalic neurons (CNs) are frequently observed in HMEG specimens. Cytomegaly in developmental brain malformations may reflect in aberrant activation of the mTOR and beta-catenin signaling cascades, known regulators of cell size. We hypothesized that there is aberrant co-expression of phospho-ribosomal S6 (P-S6) protein, a downstream effector of the mTOR cascade, as well as cyclin D1, a downstream effector of the beta-catenin pathway, in BCs and cytomegalic neurons in HMEG. We hypothesized that mutations in PTEN (a cause of HMEG associated with Proteus syndrome), TSC1 or TSC2 (tuberous sclerosis complex) genes, which are known to modulate beta-catenin and mTOR signaling could cause sporadic HMEG. Expression of cyclin D1, phospho-p70 S6 kinase (P-p70S6K, another mTOR cascade kinase), P-S6, MAP2, NeuN, or GFAP was determined by immunohistochemistry in HMEG brain tissue (n = 7 specimens). Cyclin D1, P-p70S6K, and P-S6 proteins were co-localized in BCs and CNs in the enlarged hemisphere but not in the unaffected hemisphere or in morphologically normal tissue. Cyclin D1 and P-S6 proteins were not detected in GFAP-labeled astrocytes. Sequencing of PTEN, TSC1, and TSC2 genes in cytomegalic cells co-expressing cyclin D1 and P-S6 proteins did not reveal mutations. Selective expression of cyclin D1 and P-S6 in cytomegalic cells in HMEG suggests co-activation of the beta-catenin and mTOR cascades. PTEN, TSC1, or TSC2 gene mutations were not detected suggesting that sporadic HMEG is distinct from HMEG associated with Proteus syndrome or tuberous sclerosis complex.
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Karin
authors.initials: K
authors.lastname: Boer
authors.forename: Marianna
authors.initials: M
authors.lastname: Baybis
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.forename: Peter
authors.initials: P
authors.lastname: Crino
mesh_terms: D034961:Antigens, Nuclear / Q000096:biosynthesis; D001921:Brain / Q000378:metabolism*; D002675:Child, Preschool; D019938:Cyclin D1 / Q000096:biosynthesis*; D005260:Female; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019893:Ribosomal Protein S6 Kinases / Q000096:biosynthesis*; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; D005904:Glial Fibrillary Acidic Protein; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; C506808:neuronal nuclear antigen NeuN, human; D019938:Cyclin D1; D011494:Protein Kinases; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human