Functional whole-genome analysis identifies Polo-like kinase 2 and poliovirus receptor as essential for neuronal differentiation upstream of the negative regulator alphaB-crystallin.
This study aimed at identifying transcriptional changes associated to neuronal differentiation induced by six distinct stimuli using whole-genome microarray hybridization analysis. Bioinformatics analyses revealed the clustering of these six stimuli into two categories, suggesting separate gene/pathway dependence. Treatment with specific inhibitors demonstrated the requirement of both Janus kinase and microtubule-associated protein kinase activation to trigger differentiation with nerve growth factor (NGF) and dibutyryl cAMP. Conversely, activation of protein kinase A, phosphatidylinositol-3-kinase alpha, and mammalian target of rapamycin, although required for dibutyryl cAMP-induced differentiation, exerted a negative feedback on NGF-induced differentiation. We identified Polo-like kinase 2 (Plk2) and poliovirus receptor (PVR) as indispensable for NGF-driven neuronal differentiation and alphaB-crystallin (Cryab) as an inhibitor of this process. Silencing of Plk2 or PVR blocked NGF-triggered differentiation and Cryab down-regulation, while silencing of Cryab enhanced NGF-induced differentiation. Our results position both Plk2 and PVR upstream of the negative regulator Cryab in the pathway(s) leading to neuronal differentiation triggered by NGF.
Draghetti
Cristina
C
Departments of Target Research, Merck Serono International S.A. 9, Chemin de Mines, 1202 Geneva, Switzerland.
Salvat
Catherine
C
Zanoguera
Francisca
F
Curchod
Marie-Laure
ML
Vignaud
Chloé
C
Peixoto
Helene
H
Di Cara
Alessandro
A
Fischer
David
D
Dhanabal
Mohanraj
M
Andreas
Goutopoulos
G
Abderrahim
Hadi
H
Rommel
Christian
C
Camps
Montserrat
M
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D019295:Computational Biology; D020869:Gene Expression Profiling; D016678:Genome; D006801:Humans; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D011991:Receptors, Virus; D038203:alpha-Crystallin B Chain; C066100:poliovirus receptor; D020932:Nerve Growth Factor; D017346:Protein Serine-Threonine Kinases; C530504:Plk2 protein, rat
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