Back to Search Start Over

ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size.

Authors :
Rotem Kadir
Tamar Harel
Barak Markus
Yonatan Perez
Anna Bakhrat
Idan Cohen
Michael Volodarsky
Miora Feintsein-Linial
Elana Chervinski
Joel Zlotogora
Sara Sivan
Ramon Y Birnbaum
Uri Abdu
Stavit Shalev
Ohad S Birk
Source :
PLoS Genetics, Vol 12, Iss 3, p e1005919 (2016)
Publication Year :
2016
Publisher :
Public Library of Science (PLoS), 2016.

Abstract

Primary microcephaly is a congenital neurodevelopmental disorder of reduced head circumference and brain volume, with fewer neurons in the cortex of the developing brain due to premature transition between symmetrical and asymmetrical cellular division of the neuronal stem cell layer during neurogenesis. We now show through linkage analysis and whole exome sequencing, that a dominant mutation in ALFY, encoding an autophagy scaffold protein, causes human primary microcephaly. We demonstrate the dominant effect of the mutation in drosophila: transgenic flies harboring the human mutant allele display small brain volume, recapitulating the disease phenotype. Moreover, eye-specific expression of human mutant ALFY causes rough eye phenotype. In molecular terms, we demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal specifically of aggregates of DVL3 and not of Dvl1 or Dvl2. Thus, autophagic attenuation of Wnt signaling through removal of Dvl3 aggregates by ALFY acts in determining human brain size.

Subjects

Subjects :
Genetics
QH426-470

Details

Language :
English
ISSN :
15537390 and 15537404
Volume :
12
Issue :
3
Database :
Directory of Open Access Journals
Journal :
PLoS Genetics
Publication Type :
Academic Journal
Accession number :
edsdoj.01db379f64c84cf18be33060206d37ff
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pgen.1005919