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

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

doi:10.1371/journal.pgen.1005919

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

PLoS Genet. 2016 Mar 23;12(3):e1005919. doi: 10.1371/journal.pgen.1005919. eCollection 2016 Mar.

Authors

Affiliations

¹ The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel.
² Department of Life Sciences, Ben Gurion University, Beer Sheva, Israel.
³ Genetics Institute, HaEmek Medical Center, Afula, Israel.
⁴ Department of Community Genetics, Public Health Services, Ministry of Health, Jerusalem, Israel.
⁵ Genetics Institute, Soroka University Medical Center, Ben Gurion University, Beer Sheva, Israel.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Animals
Animals, Genetically Modified
Autophagy-Related Proteins
Brain / growth & development
Brain / metabolism
Brain / pathology
Dishevelled Proteins
Drosophila
Genetic Linkage
High-Throughput Nucleotide Sequencing
Humans
Membrane Proteins / genetics*
Microcephaly / genetics*
Microcephaly / pathology
Mutation
Organ Size / genetics
Phosphoproteins / genetics*
Transcription Factors / genetics*
Wnt Signaling Pathway / genetics

Substances

Adaptor Proteins, Signal Transducing
Autophagy-Related Proteins
DVL1 protein, human
DVL2 protein, human
DVL3 protein, human
Dishevelled Proteins
Membrane Proteins
Phosphoproteins
Transcription Factors
WDFY3 protein, human

Grants and funding

Funding for this research was provided by Teva Pharmaceutical Industries Ltd. as part of the Israeli National Network of Excellence in Neuroscience (NNE) established by Teva, and by the Legacy Heritage Bio-Medical Program of the Israel Science Foundation (grant no. 1814/13). RK was financed through a Teva Israeli National Network of Excellence in Neuroscience (NNE) grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.