title: ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size.
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.
authors.affiliation: 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.
authors.forename: Rotem
authors.initials: R
authors.lastname: Kadir
authors.affiliation: 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.
authors.forename: Tamar
authors.initials: T
authors.lastname: Harel
authors.affiliation: 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.
authors.forename: Barak
authors.initials: B
authors.lastname: Markus
authors.affiliation: 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.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Perez
authors.affiliation: Department of Life Sciences, Ben Gurion University, Beer Sheva, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Bakhrat
authors.affiliation: 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.
authors.forename: Idan
authors.initials: I
authors.lastname: Cohen
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Volodarsky
authors.affiliation: 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.
authors.forename: Miora
authors.initials: M
authors.lastname: Feintsein-Linial
authors.affiliation: Genetics Institute, HaEmek Medical Center, Afula, Israel.
authors.forename: Elana
authors.initials: E
authors.lastname: Chervinski
authors.affiliation: Department of Community Genetics, Public Health Services, Ministry of Health, Jerusalem, Israel.
authors.forename: Joel
authors.initials: J
authors.lastname: Zlotogora
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Sivan
authors.affiliation: Department of Life Sciences, Ben Gurion University, Beer Sheva, Israel.
authors.forename: Ramon Y
authors.initials: RY
authors.lastname: Birnbaum
authors.affiliation: Department of Life Sciences, Ben Gurion University, Beer Sheva, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Abdu
authors.affiliation: Genetics Institute, HaEmek Medical Center, Afula, Israel.
authors.forename: Stavit
authors.initials: S
authors.lastname: Shalev
authors.affiliation: 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.|Genetics Institute, Soroka University Medical Center, Ben Gurion University, Beer Sheva, Israel.
authors.forename: Ohad S
authors.initials: OS
authors.lastname: Birk
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D000071183:Autophagy-Related Proteins; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D000072261:Dishevelled Proteins; D004330:Drosophila; D008040:Genetic Linkage; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009929:Organ Size / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; C000606578:DVL1 protein, human; C000606581:DVL2 protein, human; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; C499825:WDFY3 protein, human