Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth.
In the developing nervous system, Id2 (inhibitor of DNA binding 2, also known as inhibitor of differentiation 2) enhances cell proliferation, promotes tumour progression and inhibits the activity of neurogenic basic helix-loop-helix (bHLH) transcription factors. The anaphase promoting complex/cyclosome and its activator Cdh1 (APC/C(Cdh1)) restrains axonal growth but the targets of APC/C(Cdh1) in neurons are unknown. Id2 and other members of the Id family are very unstable proteins that are eliminated as cells enter the quiescent state, but how they are targeted for degradation has remained elusive. Here we show that Id2 interacts with the core subunits of APC/C and Cdh1 in primary neurons. APC/C(Cdh1) targets Id2 for degradation through a destruction box motif (D box) that is conserved in Id1 and Id4. Depletion of Cdh1 stabilizes Id proteins in neurons, whereas Id2 D-box mutants are impaired for Cdh1 binding and remain stable in cells that exit from the cell cycle and contain active APC/C(Cdh1). Mutants of the Id2 D box enhance axonal growth in cerebellar granule neurons in vitro and in the context of the cerebellar cortex, and overcome the myelin inhibitory signals for growth. Conversely, activation of bHLH transcription factors induces a cluster of genes with potent axonal inhibitory functions including the gene coding for the Nogo receptor, a key transducer of myelin inhibition. Degradation of Id2 in neurons permits the accumulation of the Nogo receptor, thereby linking APC/C(Cdh1) activity with bHLH target genes for the inhibition of axonal growth. These findings indicate that deregulated Id activity might be useful to reprogramme quiescent neurons into the axonal growth mode.
Lasorella
Anna
A
Institute for Cancer Genetics, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Stegmüller
Judith
J
Guardavaccaro
Daniele
D
Liu
Guangchao
G
Carro
Maria S
MS
Rothschild
Gerson
G
de la Torre-Ubieta
Luis
L
Pagano
Michele
M
Bonni
Azad
A
Iavarone
Antonio
A
D064173:Anaphase-Promoting Complex-Cyclosome; D001369:Axons / Q000502:physiology*; D002453:Cell Cycle; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism*; D008938:Mitosis; D011499:Protein Processing, Post-Translational; D013379:Substrate Specificity; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome