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{"title"=>"ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size", "type"=>"journal", "authors"=>[{"first_name"=>"Rotem", "last_name"=>"Kadir", "scopus_author_id"=>"55232920300"}, {"first_name"=>"Tamar", "last_name"=>"Harel", "scopus_author_id"=>"6602592220"}, {"first_name"=>"Barak", "last_name"=>"Markus", "scopus_author_id"=>"36699996900"}, {"first_name"=>"Yonatan", "last_name"=>"Perez", "scopus_author_id"=>"55792345100"}, {"first_name"=>"Anna", "last_name"=>"Bakhrat", "scopus_author_id"=>"15756953300"}, {"first_name"=>"Idan", "last_name"=>"Cohen", "scopus_author_id"=>"8389571200"}, {"first_name"=>"Michael", "last_name"=>"Volodarsky", "scopus_author_id"=>"6507651873"}, {"first_name"=>"Miora", "last_name"=>"Feintsein-Linial", "scopus_author_id"=>"57188701120"}, {"first_name"=>"Elana", "last_name"=>"Chervinski", "scopus_author_id"=>"10939111800"}, {"first_name"=>"Joel", "last_name"=>"Zlotogora", "scopus_author_id"=>"56276042400"}, {"first_name"=>"Sara", "last_name"=>"Sivan", "scopus_author_id"=>"12809517900"}, {"first_name"=>"Ramon Y.", "last_name"=>"Birnbaum", "scopus_author_id"=>"14026355900"}, {"first_name"=>"Uri", "last_name"=>"Abdu", "scopus_author_id"=>"6603305609"}, {"first_name"=>"Stavit", "last_name"=>"Shalev", "scopus_author_id"=>"7005556123"}, {"first_name"=>"Ohad S.", "last_name"=>"Birk", "scopus_author_id"=>"6701619815"}], "year"=>2016, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537404", "doi"=>"10.1371/journal.pgen.1005919", "sgr"=>"84962361592", "scopus"=>"2-s2.0-84962361592", "pmid"=>"27008544", "pui"=>"609631175"}, "id"=>"c3f8eabd-f36a-3bd9-8c96-2519ded7e0c3", "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.", "link"=>"http://www.mendeley.com/research/alfycontrolled-dvl3-autophagy-regulates-wnt-signaling-determining-human-brain-size", "reader_count"=>31, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>4, "Researcher"=>1, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>1, "Student > Master"=>2, "Other"=>3, "Student > Bachelor"=>3, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>4, "Researcher"=>1, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>1, "Student > Master"=>2, "Other"=>3, "Student > Bachelor"=>3, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>13, "Agricultural and Biological Sciences"=>11, "Medicine and Dentistry"=>3, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>11}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>13}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>1, "Poland"=>1, "Germany"=>1}, "group_count"=>1}

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• http://doi.org/10.1016/j.semcdb.2018.01.013
• http://doi.org/10.1038/s41598-018-29421-7
• http://doi.org/10.1038/mp.2016.228
• http://doi.org/10.7554/eLife.14810
• http://doi.org/10.1042/NS20180134
• http://doi.org/10.1146/annurev-genom-083117-021441
• http://doi.org/10.1038/s41419-019-1763-2
• http://doi.org/10.1093/cvr/cvy285
• http://doi.org/10.1038/s41598-017-12734-4
• http://doi.org/10.1093/brain/awz198
• http://doi.org/10.1017/S0016672318000046
• http://doi.org/10.1371/journal.pbio.2006613
• http://doi.org/10.3390/cells9010049
• http://doi.org/10.1016/j.pneurobio.2017.03.007
• http://doi.org/10.1016/j.cell.2018.09.048
• http://doi.org/10.1038/s41431-019-0444-z
• http://doi.org/10.3390/children4060047
• http://doi.org/10.1016/j.neuron.2019.12.003
• http://doi.org/10.1136/jmedgenet-2018-105471
• http://doi.org/10.1016/j.nbd.2019.05.008
• http://doi.org/10.1093/brain/awz004
• http://doi.org/10.1016/j.neulet.2018.04.017

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• {"id"=>"712695628879429632", "text"=>"#PLoS #Genetics: ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size https://t.co/FpgOntx6sO", "created_at"=>"2016-03-23T17:40:53Z", "user"=>"whatDNAtest", "user_name"=>"Carlos Esteban PhD", "user_profile_image"=>"http://pbs.twimg.com/profile_images/2209463838/c-azul-negro2_normal.jpg"}
• {"id"=>"712700899676827648", "text"=>"#Genes#Mutations#Car ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining… https://t.co/bynmF08fFM", "created_at"=>"2016-03-23T18:01:50Z", "user"=>"orlmedicine", "user_name"=>"Alex Sfakianakis", "user_profile_image"=>"http://pbs.twimg.com/profile_images/649206418852085760/kDVrKW-R_normal.png"}
• {"id"=>"712733379259736065", "text"=>"#Genes#Mutations#Car ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining… https://t.co/iC1wdPMYFQ", "created_at"=>"2016-03-23T20:10:54Z", "user"=>"orlmedicine", "user_name"=>"Alex Sfakianakis", "user_profile_image"=>"http://pbs.twimg.com/profile_images/649206418852085760/kDVrKW-R_normal.png"}

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Figshare

• {"files"=>["https://ndownloader.figshare.com/files/4875049"], "description"=>"<p><b>A. The affected Arab Israeli kindred and fine mapping:</b> Haplotype shared by affected individuals is highlighted in light gray shading. Note that the haplotype of healthy individual II:6 determines the minimal shared ~9 Mbp disease-associated locus (rectangular black box) between markers D4S3243 and D4S2460. Haplotypes for individual I:2 (DNA not available) were reconstructed using data of two successive generations. Marker positions are given in Mbp. <b>B. The ALFY g.Chr4:85636503G>A, c.7909C>T, p.R2637W mutation.</b> Sanger sequencing of healthy (III:3) and affected (II:4) individuals. <b>C. Conservation of <i>ALFY</i> throughout evolution.</b> Substituted Arginine (black box) is extremely conserved and is located within a conserved PH domain. <b>D. Structural prediction of the mutated ALFY PH-BEACH domain based on the solved structure of PH-BEACH domain of neurobeachin</b>. Modeling suggests that the Arginine residue protrudes to the predicted phospholipid binding pockets and is presumably critical for the domain function.</p>", "links"=>[], "tags"=>["DVL", "removal", "Human Brain Size", "autophagy scaffold protein", "Dvl 3 aggregates", "Wnt", "brain volume", "mutation", "microcephaly", "ALFY", "phenotype"], "article_id"=>3134416, "categories"=>["Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Evolutionary Biology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Science Policy", "Infectious Diseases"], "users"=>["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"=>"https://dx.doi.org/10.1371/journal.pgen.1005919.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Pedigree_of_studied_kindred_and_the_i_ALFY_i_mutation_/3134416", "title"=>"Pedigree of studied kindred and the <i>ALFY</i> mutation.", "pos_in_sequence"=>1, "defined_type"=>1, "published_date"=>"2016-03-23 06:11:48"}
• {"files"=>["https://ndownloader.figshare.com/files/4875196"], "description"=>"<p>Proper embryonic brain development and size are achieved through clonal expansion of apical progenitors (APs), followed by expansion of basal progenitors (BPs). The first step is clonal expansion of the AP cell layer: AP cells undergo a series of Wnt signaling-induced proliferative symmetrical divisions. Due to Wnt signaling activation, DVL3 levels increase and the β-catenin destruction complex is recruited to the membrane, preventing it from phosphorylating β-catenin, leading to accumulation of β-catenin in the cytoplasm and eventually in the nucleus. This triggers activation of Wnt signaling-specific genes that allow the APs to further proliferate and maintain their progenitor identity, generating the first clonal expansion in the developing brain. Once there is sufficient number of AP cells, ALFY attenuates Wnt signaling by autophagy-mediated removal of DVL3, allowing the β-catenin destruction complex to phosphorylate β-catenin, resulting in its removal from the cytoplasm. This attenuation of the Wnt signaling enables the cells to start asymmetric differentiative divisions, generating the second critical layer in the developing brain, the BPs. The BPs will continue to proliferate and eventually differentiate to generate neuronal cells. In the absence of appropriate ALFY activity (right panel) DVL3 levels remain high, resulting in elevated β-catenin levels and high activation of the Wnt signaling pathway. This lack of attenuation of Wnt signaling prevents proper generation of the BP cell layer and therefore reduces the generation of differentiated neurons. We believe that this locks the AP cells in successive rounds of symmetrical proliferative divisions, further expanding their population at the expense of generating the crucial BP cell layer, resulting in major reduction of BPs. Since the AP layer is confined in space, this expansion of APs cells is limited and will not compensate for the lack of BPs. It is the BP cell layer that demonstrates the most significant difference between primates and rodents and is believed to be responsible for determining the final size of the primate brain [<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005919#pgen.1005919.ref003\" target=\"_blank\">3</a>]. Thus, lack of BP cells in the developing brain eventually leads to reduced number of neurons and microcephaly.</p>", "links"=>[], "tags"=>["DVL", "removal", "Human Brain Size", "autophagy scaffold protein", "Dvl 3 aggregates", "Wnt", "brain volume", "mutation", "microcephaly", "ALFY", "phenotype"], "article_id"=>3134530, "categories"=>["Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Evolutionary Biology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Science Policy", "Infectious Diseases"], "users"=>["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"=>"https://dx.doi.org/10.1371/journal.pgen.1005919.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Proposed_model_ALFY_mediates_proper_brain_development_through_DVL3_autophagy_mediated_precise_control_of_the_canonical_Wnt_signaling_pathway_/3134530", "title"=>"Proposed model—ALFY mediates proper brain development through DVL3-autophagy-mediated precise control of the canonical Wnt signaling pathway.", "pos_in_sequence"=>5, "defined_type"=>1, "published_date"=>"2016-03-23 06:11:48"}
• {"files"=>["https://ndownloader.figshare.com/files/4875106"], "description"=>"<p><b>A. Aggregate encapsulation and removal by hALFY.</b> HEk293T cells were co-transfected with EGFP-Htt-Poly103Q and tdTomato hALFY (wild type and mutant) (a-h). There was no significant difference in total amount of aggregates between wild type hALFY to mutant (a, e). Both wild type hALFY (b-d) and mutant hALFY (f-h) can identify and encapsulate aggregated Poly103Q. <b>B. Cloning of the hALFY constructs.</b> Schematic representation of the C-terminal end of <i>hALFY</i> constructs containing all functional domains of the protein. Four hALFY constructs were created: wild type, mutant, Δ-FYVE and mock tagged with N-terminal FLAG or tdTomato epitopes. <b>C. TOP Flash reporter assay demonstrates that wild type hALFY attenuates Wnt signaling.</b> Neuroblastoma cells were co-transfected with TOP Flash reporter assay constructs as well as the different hALFY plasmids (wild type, mutant, Δ-FYVE and hALFY-mock). Cells expressing wild type hALFY demonstrate a reduction of approximately 40% in luciferase expression relative to mutant hALFY and Δ-FYVE or mock controls (student t test, n = 3, P_value = 0.0005). Moreover, this attenuation is achieved probably in an autophagy dependent manner as could be seen by the addition of autophagy inhibitor wortmannin. <b>D. ALFY attenuates the canonical Wnt signaling pathway.</b> Cells over expressing the WT ALFY demonstrate lower levels (approximately 80% reduction, student t test, n = 3, P_value = 0.0028) of endogenous β-catenin.</p>", "links"=>[], "tags"=>["DVL", "removal", "Human Brain Size", "autophagy scaffold protein", "Dvl 3 aggregates", "Wnt", "brain volume", "mutation", "microcephaly", "ALFY", "phenotype"], "article_id"=>3134452, "categories"=>["Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Evolutionary Biology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Science Policy", "Infectious Diseases"], "users"=>["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"=>"https://dx.doi.org/10.1371/journal.pgen.1005919.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Htt_Poly103Q_aggregate_removal_and_Wnt_signaling_attenuation_by_i_hALFY_i_protein_/3134452", "title"=>"Htt-Poly103Q aggregate removal and Wnt signaling attenuation by <i>hALFY</i> protein.", "pos_in_sequence"=>3, "defined_type"=>1, "published_date"=>"2016-03-23 06:11:48"}
• {"files"=>["https://ndownloader.figshare.com/files/4875082"], "description"=>"<p><b>A</b>. <b>Cloning construct for transgenic flies experiments.</b> The C Terminal part, containing all functional domains of human <i>ALFY</i>, was cloned in-frame with an EGFP sequence at the 3' end to form a fusion protein. An upstream activating sequence (UAS) was added at the 5' end of the sequence for controlled expression. <b>B. Eye phenotype.</b> Expression of both wild type (WT) and mutant <i>hALFY</i> alleles was driven with the GMR-GAL4 promoter. Fly eyes were analyzed in terms of pigmentation, size, shape and surface texture, and representative digital eye images were taken. Higher resolution images (SEM) obtained at X400 and X1200 magnification. While all original hALFY wild type, mutant and GMR driver lines, as well as the GMR hALFY wild type driven expression resulted in normal eye development (a-d), the GMR mutant hALFY driven expression resulted in a severe eye phenotype (e). Mutant eyes are disorganized, and malformed with abnormal omatids formation and orientation. Omatids appear to be fused and bristle morphology and distribution is abrupted with missing or fused bristles. <b>C. Brain phenotype.</b> Brains of flies of actin-driven expression of wild type <i>hALFY</i>-EGFP (a-c) and mutant <i>hALFY</i>-EGFP (e-f). Brains of wild type and mutant flies were dissected and visualized with confocal microscope in bright field (a, d) and 488nm filter (b, e) at X20 magnification. As opposed to the wild type allele, homogenous actin-driven expression of the mutant allele resulted in the formation of smaller, less organized and denser brains (a, d). Mutant brains were 40–60% smaller in volume than wild type (t test two tailed analysis, wild type n = 18, Mut n = 31, P_value<0.0001). Expression profiling using the EGFP tag, clearly demonstrates that the mutant protein tends to accumulate in the brains of mutant flies in large clusters of cells (e–white arrows) as opposed to the expression pattern in the wild type (b–white arrows). Mutant cells are dispersed throughout the brain and appear to be smaller in size, less elongated and greater in number than the wild type.</p>", "links"=>[], "tags"=>["DVL", "removal", "Human Brain Size", "autophagy scaffold protein", "Dvl 3 aggregates", "Wnt", "brain volume", "mutation", "microcephaly", "ALFY", "phenotype"], "article_id"=>3134437, "categories"=>["Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Evolutionary Biology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Science Policy", "Infectious Diseases"], "users"=>["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"=>"https://dx.doi.org/10.1371/journal.pgen.1005919.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Mutant_i_hALFY_i_causes_dominant_phenotypes_in_Drosophila_/3134437", "title"=>"Mutant <i>hALFY</i> causes dominant phenotypes in Drosophila.", "pos_in_sequence"=>2, "defined_type"=>1, "published_date"=>"2016-03-23 06:11:48"}
• {"files"=>["https://ndownloader.figshare.com/files/4875160"], "description"=>"<p><b>A. Cloning of the different DVLs.</b> The three different <i>DVLs</i> were PCR-amplified from brain cDNA and cloned in frame with an N-terminal FLAG tag and a C-terminal EGFP. <b>B. Co-localization of hALFY with the different DVLs.</b> Neuroblastoma cells were co-transfected with the different DVLs (1, 2 & 3) as well as tdTomato hALFY wild type/mutant constructs. Both wild type and mutant hALFY co-localize specifically with DVL3 (c-i, c-ii) and not DVL1 (a-i, a-ii) or DVL2 (b-i,b-ii). Minimal co-localization with DVL1 was visible (a-i, a-ii), and could be due to the strong over expression. <b>C. Western blot analysis of DVL over expression.</b> Neuroblastoma cells were co-transfected with the different DVLs and FLAG hALFY (wild type, mutant, Δ-FYVE and mock). After 24 hours, cells were treated with cycloheximide to arrest further de-novo protein synthesis. WB analysis reveals that hALFY wild type removes aggregated DVL3 (student t test, n = 3, P_value = 0.04) yet not DVL1 or DVL2. DVL3 protein accumulated in hALFY mutant expressing cells. <b>D. Western blot analysis of endogenous DVLs.</b> Following transfection of the different FLAG hALFY constructs, neuroblastoma cells were incubated with Wnt3a conditioned medium for 8 hours and harvested for WB analysis. hALFY wild type specifically removed endogenous DVL3 aggregates, yet not DVL1 or DVL2. This effect was inhibited by wortmannin, indicating that hALFY removes DVL3 aggregates presumably in an autophagy dependent manner (student t test, n = 3, P_value = 0.03).</p>", "links"=>[], "tags"=>["DVL", "removal", "Human Brain Size", "autophagy scaffold protein", "Dvl 3 aggregates", "Wnt", "brain volume", "mutation", "microcephaly", "ALFY", "phenotype"], "article_id"=>3134494, "categories"=>["Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Evolutionary Biology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Science Policy", "Infectious Diseases"], "users"=>["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"=>"https://dx.doi.org/10.1371/journal.pgen.1005919.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/hALFY_protein_co_localizes_with_aggregated_DVL3_and_facilitates_its_removal_/3134494", "title"=>"hALFY protein co-localizes with aggregated DVL3 and facilitates its removal.", "pos_in_sequence"=>4, "defined_type"=>1, "published_date"=>"2016-03-23 06:11:48"}

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Relative Metric

{"start_date"=>"2016-01-01T00:00:00Z", "end_date"=>"2016-12-31T00:00:00Z", "subject_areas"=>[]}

F1000Prime