Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets.
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.
Ferretti
E
E
Department of Experimental Medicine and Pathology, University La Sapienza, Roma, Italy.
Di Marcotullio
L
L
Gessi
M
M
Mattei
T
T
Greco
A
A
Po
A
A
De Smaele
E
E
Giangaspero
F
F
Riccardi
R
R
Di Rocco
C
C
Pazzaglia
S
S
Maroder
M
M
Alimandi
M
M
Screpanti
I
I
Gulino
A
A
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
D017931:DNA Primers; D053823:Hedgehog Proteins; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4