title: Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets.
abstract: Medulloblastoma (MB) results from aberrant development of cerebellar neurons in which altered hedgehog (Hh) signalling plays a major role. We investigated the possible influence of Hh signalling on ErbB-receptor expression in MB, in particular that of the ErbB-4 CYT-1 and CYT-2 isoforms generated by alternative splicing of the cytoplasmic domain. ErbB-4 expression was downregulated in Hh-induced MBs from Patched-1(+/-) mice. Hh signalling (reflected by enhanced expression of the Gli1 transcription factor) inhibited ErbB-4 expression in mouse cerebellar granule progenitors and human MB cells. Analysis of 26 human primary MBs revealed a subset of 11 tumors characterized by low Gli1 levels, upregulated ErbB-4 expression and increased CYT-1:CYT-2 ratios. Interestingly, CYT-1 and Gli1 levels were inversely correlated. ErbB-4 CYT-1 and CYT-2 had different phenotypic effects in cultured MB cells: in response to neuregulin treatment, CYT-2 overexpression inhibited proliferation whereas CYT-1, which includes a phosphatidylinositol 3-kinase (PI3K)-binding site that is missing in CYT-2, enhanced resistance to starvation- and etoposide-induced apoptosis by activating PI3K/Akt signalling. CYT-1:CYT-2 ratios displayed correlation with tumor histotype and ErbB-2 levels, which are established prognostic indices for MB. These findings demonstrate that low-level Hh signalling in human MB is associated with the selective maintenance of high ErbB-4 CYT-1 expression, an alteration that exerts tumor-promoting effects.
authors.affiliation: Department of Experimental Medicine and Pathology, University La Sapienza, Roma, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ferretti
authors.forename: L
authors.initials: L
authors.lastname: Di Marcotullio
authors.forename: M
authors.initials: M
authors.lastname: Gessi
authors.forename: T
authors.initials: T
authors.lastname: Mattei
authors.forename: A
authors.initials: A
authors.lastname: Greco
authors.forename: A
authors.initials: A
authors.lastname: Po
authors.forename: E
authors.initials: E
authors.lastname: De Smaele
authors.forename: F
authors.initials: F
authors.lastname: Giangaspero
authors.forename: R
authors.initials: R
authors.lastname: Riccardi
authors.forename: C
authors.initials: C
authors.lastname: Di Rocco
authors.forename: S
authors.initials: S
authors.lastname: Pazzaglia
authors.forename: M
authors.initials: M
authors.lastname: Maroder
authors.forename: M
authors.initials: M
authors.lastname: Alimandi
authors.forename: I
authors.initials: I
authors.lastname: Screpanti
authors.forename: A
authors.initials: A
authors.lastname: Gulino
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D003593:Cytoplasm / Q000378:metabolism*; D017931:DNA Primers; D066246:ErbB Receptors / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000145:classification* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011379:Prognosis; D066247:Receptor, ErbB-4; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D053823:Hedgehog Proteins; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4