Unkempt Is Negatively Regulated by mTOR and Uncouples Neuronal Differentiation from Growth Control
Publication Date
September 11, 2014
Journal
PLOS Genetics
Authors
Amélie Avet Rochex, Nancy Carvajal, Christina P. Christoforou, Kelvin Yeung, et al
Volume
10
Issue
9
Pages
e1004624
DOI
https://dx.plos.org/10.1371/journal.pgen.1004624
Publisher URL
http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1004624
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/25210733
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161320
Europe PMC
http://europepmc.org/abstract/MED/25210733
Web of Science
000343009600042
Scopus
84907584446
Mendeley
http://www.mendeley.com/research/unkempt-negatively-regulated-mtor-uncouples-neuronal-differentiation-growth-control
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Mendeley | Further Information

{"title"=>"Unkempt Is Negatively Regulated by mTOR and Uncouples Neuronal Differentiation from Growth Control", "type"=>"journal", "authors"=>[{"first_name"=>"Amélie", "last_name"=>"Avet-Rochex", "scopus_author_id"=>"22133510100"}, {"first_name"=>"Nancy", "last_name"=>"Carvajal", "scopus_author_id"=>"50460946000"}, {"first_name"=>"Christina P.", "last_name"=>"Christoforou", "scopus_author_id"=>"23059539000"}, {"first_name"=>"Kelvin", "last_name"=>"Yeung", "scopus_author_id"=>"56375235800"}, {"first_name"=>"Katja T.", "last_name"=>"Maierbrugger", "scopus_author_id"=>"56375192200"}, {"first_name"=>"Carl", "last_name"=>"Hobbs", "scopus_author_id"=>"25622370000"}, {"first_name"=>"Giovanna", "last_name"=>"Lalli", "scopus_author_id"=>"6602698860"}, {"first_name"=>"Umut", "last_name"=>"Cagin", "scopus_author_id"=>"35761010400"}, {"first_name"=>"Cedric", "last_name"=>"Plachot", "scopus_author_id"=>"6507684482"}, {"first_name"=>"Helen", "last_name"=>"McNeill", "scopus_author_id"=>"7003895504"}, {"first_name"=>"Joseph M.", "last_name"=>"Bateman", "scopus_author_id"=>"36752912600"}], "year"=>2014, "source"=>"PLoS Genetics", "identifiers"=>{"scopus"=>"2-s2.0-84907584446", "pmid"=>"25210733", "sgr"=>"84907584446", "doi"=>"10.1371/journal.pgen.1004624", "isbn"=>"1553-7404 (Electronic)\\n1553-7390 (Linking)", "issn"=>"15537404", "pui"=>"600083221"}, "id"=>"12ee1002-949e-3d3d-9c87-3f9a13dc08d9", "abstract"=>"Neuronal differentiation is exquisitely controlled both spatially and temporally during nervous system development. Defects in the spatiotemporal control of neurogenesis cause incorrect formation of neural networks and lead to neurological disorders such as epilepsy and autism. The mTOR kinase integrates signals from mitogens, nutrients and energy levels to regulate growth, autophagy and metabolism. We previously identified the insulin receptor (InR)/mTOR pathway as a critical regulator of the timing of neuronal differentiation in the Drosophila melanogaster eye. Subsequently, this pathway has been shown to play a conserved role in regulating neurogenesis in vertebrates. However, the factors that mediate the neurogenic role of this pathway are completely unknown. To identify downstream effectors of the InR/mTOR pathway we screened transcriptional targets of mTOR for neuronal differentiation phenotypes in photoreceptor neurons. We identified the conserved gene unkempt (unk), which encodes a zinc finger/RING domain containing protein, as a negative regulator of the timing of photoreceptor differentiation. Loss of unk phenocopies InR/mTOR pathway activation and unk acts downstream of this pathway to regulate neurogenesis. In contrast to InR/mTOR signalling, unk does not regulate growth. unk therefore uncouples the role of the InR/mTOR pathway in neurogenesis from its role in growth control. We also identified the gene headcase (hdc) as a second downstream regulator of the InR/mTOR pathway controlling the timing of neurogenesis. Unk forms a complex with Hdc, and Hdc expression is regulated by unk and InR/mTOR signalling. Co-overexpression of unk and hdc completely suppresses the precocious neuronal differentiation phenotype caused by loss of Tsc1. Thus, Unk and Hdc are the first neurogenic components of the InR/mTOR pathway to be identified. Finally, we show that Unkempt-like is expressed in the developing mouse retina and in neural stem/progenitor cells, suggesting that the role of Unk in neurogenesis may be conserved in mammals.", "link"=>"http://www.mendeley.com/research/unkempt-negatively-regulated-mtor-uncouples-neuronal-differentiation-growth-control", "reader_count"=>39, "reader_count_by_academic_status"=>{"Researcher"=>16, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>3, "Student > Master"=>5, "Student > Bachelor"=>2}, "reader_count_by_user_role"=>{"Researcher"=>16, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>3, "Student > Master"=>5, "Student > Bachelor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Medicine and Dentistry"=>4, "Agricultural and Biological Sciences"=>23, "Neuroscience"=>3, "Psychology"=>1, "Social Sciences"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Neuroscience"=>{"Neuroscience"=>3}, "Social Sciences"=>{"Social Sciences"=>1}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>23}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1673130"], "description"=>"<p>(A, A′) An <i>unk<sup>ex24</sup>, hdc<sup>43</sup></i> double mutant clone causes a similar precocious differentiation of R1/6 phenotype (arrow) to either single mutant. (B) An <i>unk<sup>ex24</sup>, hdc<sup>43</sup></i> double mutant clone in the adult eye causes similar ommatidial rotation and morphogenesis defects to <i>unk</i> and <i>hdc</i> mutant clones. Mutant cells are marked by the lack of pigment. Black arrow indicates a mis-rotated ommatidium; red arrows indicate ommatidia with missing photoreceptors; black arrowheads indicate elliptical rhabdomeres; red arrowheads indicate split rhabdomeres. (C, C′) Overexpression of <i>hdcFL</i> does not affect the differentiation of R1/6. (D, D′) Combined overexpression of <i>unk</i> and <i>hdcFL</i> cause a delay in the differentiation of R1/6 (arrow). (E−H) Combined overexpression of <i>unk</i> and <i>hdcFL</i> affects eye development. Eyes from <i>GMR-Gal4</i> control (E), or <i>GMR-Gal4</i> driving the expression of <i>unk</i> (F), <i>hdcFL</i> (G), or <i>unk, hdcFL</i> (H) in female flies. Note the glassy appearance in (H). (I, I′) Overexpression of <i>unk</i> in a <i>Tsc1<sup>Q600X</sup></i> clone does not affect the precocious differentiation of R7 and cone cells. (J, J′) Overexpression of <i>unk</i> and <i>hdc</i> in a <i>Tsc1<sup>Q600X</sup></i> clone completely suppresses the precocious differentiation of R7 and cone cells. MARCM was used to generate clones in (A), (C), (D), (I) and (J) and so clonal cells are marked by GFP expression (green). Bar (red) marks R1/6 in (A), (C) and (D), while Prospero expression (Pros, red) marks R7 and cone cells in (I) and (J). The differentiation front is marked by a dotted line. Anterior is to the left.</p>", "links"=>[], "tags"=>["insulin receptor", "differentiation phenotypes", "spatiotemporal control", "differentiation phenotype", "Hdc expression", "Unk forms", "unk acts", "Drosophila melanogaster eye", "Tsc 1.", "mTOR kinase", "transcriptional targets", "inr", "neurogenic components", "Negatively Regulated", "Growth Control Neuronal differentiation", "Growth control", "photoreceptor neurons", "pathway", "photoreceptor differentiation", "neurogenic role", "mouse retina", "gene headcase", "Uncouples Neuronal Differentiation", "system development", "energy levels", "neurogenesis cause"], "article_id"=>1168349, "categories"=>["Uncategorised"], "users"=>["Amélie Avet-Rochex", "Nancy Carvajal", "Christina P. Christoforou", "Kelvin Yeung", "Katja T. Maierbrugger", "Carl Hobbs", "Giovanna Lalli", "Umut Cagin", "Cedric Plachot", "Helen McNeill", "Joseph M. Bateman"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004624.g006", "stats"=>{"downloads"=>0, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_unk_and_hdc_act_together_to_control_the_timing_of_photoreceptor_differentiation_/1168349", "title"=>"<i>unk</i> and <i>hdc</i> act together to control the timing of photoreceptor differentiation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:59:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1673056"], "description"=>"<p>(A) Hdc physically interacts with Unk. Venus-Unk or FLAG-HdcS were expressed alone or together in S2 cells and immunoprecipitated with GFP or FLAG antibodies. (B, B′) <i>hdc<sup>43</sup></i> mutant clones showing precocious differentiation of R1/6 (arrows), marked by the expression of Bar (red). (C-C′′′) <i>hdc<sup>43</sup></i> mutant clones showing precocious differentiation (arrow) of R7 and cone cells (marked by the expression of Prospero (red)) and decreased expression of Unk (white in (C″) and (C′′′)). The differentiation front is marked by a dotted line. (D, D′) Precocious differentiation of cone cells (marked by the expression of D-Pax2, red) in a <i>hdc<sup>43</sup></i> mutant clone. Arrow indicates cone cells that have differentiated precociously. Note also the increased expression of D-Pax2 in <i>hdc</i> mutant clones. (E, E′) Loss of <i>hdc</i> does not affect the differentiation of R3/4 (marked by the expression of Spalt (Sal, red)). (F, F′) Loss of <i>hdc</i> does not affect the differentiation of R2/5 (marked by the expression of Rough (Ro, red)). (G) <i>hdc<sup>43</sup></i> mutant clones in the adult eye cause defects in ommatidial rotation and morphogenesis. Mutant cells are marked by the lack of dark pigment. Black arrows indicate mis-rotated ommatidia; red arrows indicate ommatidia with missing photoreceptors; black arrowheads indicate elliptical rhabdomeres; red arrowhead indicates split rhabdomeres. Mutant clones are marked by loss of GFP expression (green) in (B)–(F). Anterior is to the left.</p>", "links"=>[], "tags"=>["insulin receptor", "differentiation phenotypes", "spatiotemporal control", "differentiation phenotype", "Hdc expression", "Unk forms", "unk acts", "Drosophila melanogaster eye", "Tsc 1.", "mTOR kinase", "transcriptional targets", "inr", "neurogenic components", "Negatively Regulated", "Growth Control Neuronal differentiation", "Growth control", "photoreceptor neurons", "pathway", "photoreceptor differentiation", "neurogenic role", "mouse retina", "gene headcase", "Uncouples Neuronal Differentiation", "system development", "energy levels", "neurogenesis cause"], "article_id"=>1168285, "categories"=>["Uncategorised"], "users"=>["Amélie Avet-Rochex", "Nancy Carvajal", "Christina P. Christoforou", "Kelvin Yeung", "Katja T. Maierbrugger", "Carl Hobbs", "Giovanna Lalli", "Umut Cagin", "Cedric Plachot", "Helen McNeill", "Joseph M. Bateman"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004624.g004", "stats"=>{"downloads"=>0, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hdc_physically_interacts_with_Unk_and_negatively_regulates_neurogenesis_/1168285", "title"=>"Hdc physically interacts with Unk and negatively regulates neurogenesis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:59:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1672960"], "description"=>"<p>(A) A wild-type antennal-eye imaginal disc stained with phalloidin (green) to mark F-actin at the apical surface and Prospero (red) to visualise R7 and cone cells. The left part of the disc forms the antenna, the right part the eye. Photoreceptors differentiate posterior to the morphogenetic furrow (MF), which forms an indentation in the disc that moves from posterior (P) to anterior (A). (B, B′) Precocious differentiation of R1/6 (shown by the expression of Bar, red) in <i>Tsc1<sup>Q600X</sup></i> mutant clones (arrows). (C) Schematic of the <i>unk</i> genomic region showing <i>unk</i> and adjacent genes (top) and the domain structure of the Unk protein (bottom). Exons are shown as black rectangles and non-coding regions as white rectangles. The regions deleted in each of the mutants are represented by dotted lines. Transposon insertions are represented by triangles. Conserved domains in the protein are shown as circles. (D-F′) Precocious differentiation of R1/6 (marked by Bar expression, red in (D, D′)) and R7/cone cells (marked by Prospero expression, red in (E, E′) and D-Pax2, red in (F, F′)) in <i>unk<sup>ex24</sup></i> mutant clones (arrows). Note also the increased expression of D-Pax2 in <i>unk</i> mutant clones. (G, G′) Loss of <i>unk</i> does not affect the differentiation of R3/4 (marked by the expression of Spalt (Sal, red)). (H, H′) Loss of <i>unk</i> does not affect the differentiation of R2/5 (marked by the expression of Rough (Ro, red)). (I) <i>unk<sup>ex24</sup></i> clones in the adult eye cause photoreceptor rotation and morphogenesis defects. Mutant cells are marked by the lack of dark pigment surrounding each ommatidium. Dotted line indicates the equator. Black arrows indicate mis-rotated ommatidia; red arrow indicates an ommatidum with missing photoreceptors; black arrowheads indicate elliptical rhabdomeres; red arrowheads indicate split rhabdomeres. (J-K′) The delay in differentiation of R1/6 (marked by Bar expression, red), caused by loss of <i>Rheb</i> (J, J′), is suppressed in <i>unk<sup>ex24</sup></i>, <i>Rheb<sup>2D1</sup></i> mutant clones (K, K′). Mutant clones are marked by loss of GFP expression (green) in (B), (D–H), (J) and (K) and the differentiation front is marked by a white dotted line. Anterior is to the left in all images.</p>", "links"=>[], "tags"=>["insulin receptor", "differentiation phenotypes", "spatiotemporal control", "differentiation phenotype", "Hdc expression", "Unk forms", "unk acts", "Drosophila melanogaster eye", "Tsc 1.", "mTOR kinase", "transcriptional targets", "inr", "neurogenic components", "Negatively Regulated", "Growth Control Neuronal differentiation", "Growth control", "photoreceptor neurons", "pathway", "photoreceptor differentiation", "neurogenic role", "mouse retina", "gene headcase", "Uncouples Neuronal Differentiation", "system development", "energy levels", "neurogenesis cause"], "article_id"=>1168206, "categories"=>["Uncategorised"], "users"=>["Amélie Avet-Rochex", "Nancy Carvajal", "Christina P. Christoforou", "Kelvin Yeung", "Katja T. Maierbrugger", "Carl Hobbs", "Giovanna Lalli", "Umut Cagin", "Cedric Plachot", "Helen McNeill", "Joseph M. Bateman"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004624.g001", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_An_RNAi_screen_for_neurogenic_genes_that_are_regulated_by_mTOR_signalling_identifies_unkempt_/1168206", "title"=>"An RNAi screen for neurogenic genes that are regulated by mTOR signalling identifies <i>unkempt</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:59:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1673159"], "description"=>"<p>Unk and Hdc form a complex that is negatively regulated by mTOR signalling. The Unk/Hdc complex then negatively regulates the expression of D-Pax2 and potentially other neurogenic factors to control the timing of photoreceptor differentiation. See the <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004624#s3\" target=\"_blank\">Discussion</a> for details.</p>", "links"=>[], "tags"=>["insulin receptor", "differentiation phenotypes", "spatiotemporal control", "differentiation phenotype", "Hdc expression", "Unk forms", "unk acts", "Drosophila melanogaster eye", "Tsc 1.", "mTOR kinase", "transcriptional targets", "inr", "neurogenic components", "Negatively Regulated", "Growth Control Neuronal differentiation", "Growth control", "photoreceptor neurons", "pathway", "photoreceptor differentiation", "neurogenic role", "mouse retina", "gene headcase", "Uncouples Neuronal Differentiation", "system development", "energy levels", "neurogenesis cause"], "article_id"=>1168363, "categories"=>["Uncategorised"], "users"=>["Amélie Avet-Rochex", "Nancy Carvajal", "Christina P. Christoforou", "Kelvin Yeung", "Katja T. Maierbrugger", "Carl Hobbs", "Giovanna Lalli", "Umut Cagin", "Cedric Plachot", "Helen McNeill", "Joseph M. Bateman"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004624.g008", "stats"=>{"downloads"=>9, "page_views"=>35, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_model_for_the_regulation_of_the_timing_of_neuronal_differentiation_by_the_Unk_Hdc_complex_acting_downstream_of_InR_mTOR_signalling_/1168363", "title"=>"A model for the regulation of the timing of neuronal differentiation by the Unk/Hdc complex acting downstream of InR/mTOR signalling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:59:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1673149"], "description"=>"<p>(A-A″) COS-7 cells overexpressing HA-tagged mouse <i>Unkl</i> stained for HA expression (red), Unkl expression (green) and DAPI (blue). (B) Hematoxylin and eosin (H&E) (blue) stained coronal section from a mouse E14.5 retina showing strong Unkl expression (brown) in the retina. (C, D) Serial H&E (blue) stained sagittal sections of the lateral SVZ from a P0 mouse showing Unkl expression (brown in (C)) and P-4E-BP expression (brown in (D)). (E-G″) Sagittal sections of the lateral SVZ from a P0 mouse showing Unkl expression (red in (E′, E″), (G′, G″), (F′, F″)) and NSCs (stained for GFAP, green in (E, E″)), TAPs (stained for Mash1, green in (F, F″)), or neuroblasts (stained for Dcx, green in (G, G″)). DAPI staining is shown in blue in (E″), (F″), (G″).</p>", "links"=>[], "tags"=>["insulin receptor", "differentiation phenotypes", "spatiotemporal control", "differentiation phenotype", "Hdc expression", "Unk forms", "unk acts", "Drosophila melanogaster eye", "Tsc 1.", "mTOR kinase", "transcriptional targets", "inr", "neurogenic components", "Negatively Regulated", "Growth Control Neuronal differentiation", "Growth control", "photoreceptor neurons", "pathway", "photoreceptor differentiation", "neurogenic role", "mouse retina", "gene headcase", "Uncouples Neuronal Differentiation", "system development", "energy levels", "neurogenesis cause"], "article_id"=>1168362, "categories"=>["Uncategorised"], "users"=>["Amélie Avet-Rochex", "Nancy Carvajal", "Christina P. Christoforou", "Kelvin Yeung", "Katja T. Maierbrugger", "Carl Hobbs", "Giovanna Lalli", "Umut Cagin", "Cedric Plachot", "Helen McNeill", "Joseph M. Bateman"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004624.g007", "stats"=>{"downloads"=>1, "page_views"=>34, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Unkl_is_expressed_in_the_developing_mammalian_eye_and_SVZ_/1168362", "title"=>"Unkl is expressed in the developing mammalian eye and SVZ.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:59:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1672969"], "description"=>"<p>(A) A confocal projection of a wild-type eye disc stained for Unk protein expression. Unk is expressed throughout the disc, but its expression is stronger posterior to the morphogenetic furrow (MF, arrow). Scale bar: 50 µm. (B) High magnification single confocal section of Unk expression (red) in differentiating photoreceptors. Unk has a cytoplasmic, partially punctate distribution. Prospero expression marking R7 and cone cells is shown in green. Arrowheads mark examples of puncta. N: nucleus. Scale bar: 10 µm. (C–D) Unk expression (white in (C′),(D′) and red in (D)) is decreased in <i>Tsc1<sup>Q600X</sup></i> mutant clones posterior to the MF (arrows) both in photoreceptors (C, showing apical level) and photoreceptor precursor cells (D, showing basal level), but not in clones anterior to the MF (arrowheads in (D)). Prospero expression (red in (C)) marks R7/cone cells. Mutant clones are marked by loss of GFP expression (green) in (C) and (D). Anterior is to the left.</p>", "links"=>[], "tags"=>["insulin receptor", "differentiation phenotypes", "spatiotemporal control", "differentiation phenotype", "Hdc expression", "Unk forms", "unk acts", "Drosophila melanogaster eye", "Tsc 1.", "mTOR kinase", "transcriptional targets", "inr", "neurogenic components", "Negatively Regulated", "Growth Control Neuronal differentiation", "Growth control", "photoreceptor neurons", "pathway", "photoreceptor differentiation", "neurogenic role", "mouse retina", "gene headcase", "Uncouples Neuronal Differentiation", "system development", "energy levels", "neurogenesis cause"], "article_id"=>1168216, "categories"=>["Uncategorised"], "users"=>["Amélie Avet-Rochex", "Nancy Carvajal", "Christina P. Christoforou", "Kelvin Yeung", "Katja T. Maierbrugger", "Carl Hobbs", "Giovanna Lalli", "Umut Cagin", "Cedric Plachot", "Helen McNeill", "Joseph M. Bateman"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004624.g002", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Unk_expression_is_regulated_by_Tsc1_in_differentiating_photoreceptors_/1168216", "title"=>"Unk expression is regulated by <i>Tsc1</i> in differentiating photoreceptors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:59:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1673256", "https://ndownloader.figshare.com/files/1673258", "https://ndownloader.figshare.com/files/1673260", "https://ndownloader.figshare.com/files/1673261", "https://ndownloader.figshare.com/files/1673262", "https://ndownloader.figshare.com/files/1673263", "https://ndownloader.figshare.com/files/1673264", "https://ndownloader.figshare.com/files/1673265", "https://ndownloader.figshare.com/files/1673266", "https://ndownloader.figshare.com/files/1673267", "https://ndownloader.figshare.com/files/1673268"], "description"=>"<div><p>Neuronal differentiation is exquisitely controlled both spatially and temporally during nervous system development. Defects in the spatiotemporal control of neurogenesis cause incorrect formation of neural networks and lead to neurological disorders such as epilepsy and autism. The mTOR kinase integrates signals from mitogens, nutrients and energy levels to regulate growth, autophagy and metabolism. We previously identified the insulin receptor (InR)/mTOR pathway as a critical regulator of the timing of neuronal differentiation in the <i>Drosophila melanogaster</i> eye. Subsequently, this pathway has been shown to play a conserved role in regulating neurogenesis in vertebrates. However, the factors that mediate the neurogenic role of this pathway are completely unknown. To identify downstream effectors of the InR/mTOR pathway we screened transcriptional targets of mTOR for neuronal differentiation phenotypes in photoreceptor neurons. We identified the conserved gene <i>unkempt</i> (<i>unk</i>), which encodes a zinc finger/RING domain containing protein, as a negative regulator of the timing of photoreceptor differentiation. Loss of <i>unk</i> phenocopies InR/mTOR pathway activation and <i>unk</i> acts downstream of this pathway to regulate neurogenesis. In contrast to InR/mTOR signalling, <i>unk</i> does not regulate growth. <i>unk</i> therefore uncouples the role of the InR/mTOR pathway in neurogenesis from its role in growth control. We also identified the gene <i>headcase</i> (<i>hdc</i>) as a second downstream regulator of the InR/mTOR pathway controlling the timing of neurogenesis. Unk forms a complex with Hdc, and Hdc expression is regulated by <i>unk</i> and InR/mTOR signalling. Co-overexpression of <i>unk</i> and <i>hdc</i> completely suppresses the precocious neuronal differentiation phenotype caused by loss of <i>Tsc1</i>. Thus, Unk and Hdc are the first neurogenic components of the InR/mTOR pathway to be identified. Finally, we show that Unkempt-like is expressed in the developing mouse retina and in neural stem/progenitor cells, suggesting that the role of Unk in neurogenesis may be conserved in mammals.</p></div>", "links"=>[], "tags"=>["insulin receptor", "differentiation phenotypes", "spatiotemporal control", "differentiation phenotype", "Hdc expression", "Unk forms", "unk acts", "Drosophila melanogaster eye", "Tsc 1.", "mTOR kinase", "transcriptional targets", "inr", "neurogenic components", "Negatively Regulated", "Growth Control Neuronal differentiation", "Growth control", "photoreceptor neurons", "pathway", "photoreceptor differentiation", "neurogenic role", "mouse retina", "gene headcase", "Uncouples Neuronal Differentiation", "system development", "energy levels", "neurogenesis cause"], "article_id"=>1168438, "categories"=>["Uncategorised"], "users"=>["Amélie Avet-Rochex", "Nancy Carvajal", "Christina P. Christoforou", "Kelvin Yeung", "Katja T. Maierbrugger", "Carl Hobbs", "Giovanna Lalli", "Umut Cagin", "Cedric Plachot", "Helen McNeill", "Joseph M. Bateman"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004624.s001", "https://dx.doi.org/10.1371/journal.pgen.1004624.s002", "https://dx.doi.org/10.1371/journal.pgen.1004624.s003", "https://dx.doi.org/10.1371/journal.pgen.1004624.s004", "https://dx.doi.org/10.1371/journal.pgen.1004624.s005", "https://dx.doi.org/10.1371/journal.pgen.1004624.s006", "https://dx.doi.org/10.1371/journal.pgen.1004624.s007", "https://dx.doi.org/10.1371/journal.pgen.1004624.s008", "https://dx.doi.org/10.1371/journal.pgen.1004624.s009", "https://dx.doi.org/10.1371/journal.pgen.1004624.s010", "https://dx.doi.org/10.1371/journal.pgen.1004624.s011"], "stats"=>{"downloads"=>18, "page_views"=>37, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Unkempt_Is_Negatively_Regulated_by_mTOR_and_Uncouples_Neuronal_Differentiation_from_Growth_Control_/1168438", "title"=>"Unkempt Is Negatively Regulated by mTOR and Uncouples Neuronal Differentiation from Growth Control", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-09-11 02:59:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1673004"], "description"=>"<p>(A–C) Phosphohistone H3 expression (PH3, green) posterior to the MF (arrowheads) is similar in eye discs from control, homozygous <i>unk<sup>ex24</sup></i>, or transheterozygous <i>unk<sup>ex24</sup>/unk<sup>Df</sup></i> larvae. (D–F) Examples of control, <i>unk<sup>ex24</sup></i> or <i>Tsc1<sup>Q600X</sup></i> clones in the eye disc. Homozygous mutant cells are marked by the loss of GFP (green) and the adjacent twin spot (ts) has stronger GFP expression than the surrounding heterozygous tissue. (G) Quantification of mutant clone versus twin spot size (n = 7 clones for each genotype). (H) Quantification of photoreceptor cell area (control n = 11, <i>Tsc1<sup>Q600X</sup></i> n = 17, <i>unk<sup>ex24</sup></i> n = 15, <i>hdc<sup>43</sup></i> n = 27, <i>unk, hdc</i> overexpression (o/e) n = 17). (I–K) Representative examples of individual cells within control, <i>unk<sup>ex24</sup></i> or <i>Tsc1<sup>Q600X</sup></i> MARCM clones in the eye disc expressing membrane-tagged GFP (green) and stained for Bar expression (red). Note the larger size of <i>Tsc1</i> mutant cells in (K). Scale bar: 2 µm. (L–N) Phospho-AKT expression (red in (L),(M),(N) and white in (L′),(M′),(N′)) is not changed in control (L, L′) or <i>unk<sup>ex24</sup></i> mutant clones (M, M′), but is decreased in <i>Tsc1<sup>Q600X</sup></i> mutant clones (N, N′) in the eye disc. Clones marked by loss of GFP expression (green). Anterior is to the left. Data are represented as mean +/− SEM, ***p≤0.001.</p>", "links"=>[], "tags"=>["insulin receptor", "differentiation phenotypes", "spatiotemporal control", "differentiation phenotype", "Hdc expression", "Unk forms", "unk acts", "Drosophila melanogaster eye", "Tsc 1.", "mTOR kinase", "transcriptional targets", "inr", "neurogenic components", "Negatively Regulated", "Growth Control Neuronal differentiation", "Growth control", "photoreceptor neurons", "pathway", "photoreceptor differentiation", "neurogenic role", "mouse retina", "gene headcase", "Uncouples Neuronal Differentiation", "system development", "energy levels", "neurogenesis cause"], "article_id"=>1168243, "categories"=>["Uncategorised"], "users"=>["Amélie Avet-Rochex", "Nancy Carvajal", "Christina P. Christoforou", "Kelvin Yeung", "Katja T. Maierbrugger", "Carl Hobbs", "Giovanna Lalli", "Umut Cagin", "Cedric Plachot", "Helen McNeill", "Joseph M. Bateman"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004624.g003", "stats"=>{"downloads"=>0, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_unk_does_not_regulate_cell_growth_/1168243", "title"=>"<i>unk</i> does not regulate cell growth.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:59:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1673097"], "description"=>"<p>(A) A confocal projection of a wild-type eye disc stained for Hdc protein expression showing Hdc expression is enriched posterior to the morphogenetic furrow (MF). Scale bar: 50 µm. (B) High magnification single confocal section of Hdc expression (green) in differentiating photoreceptors showing cytoplasmic localisation. Bar staining marking R1/6 is shown in red. N: nucleus. Scale bar: 10 µm. (C, C′) Hdc expression (red in (C) and white in (C′)) is increased in <i>unk<sup>ex24</sup></i> mutant clones. (D, D′) Close up of boxed region in (C) showing that Hdc expression (red) is increased in the <i>unk<sup>ex24</sup></i> mutant clone behind the differentiation front for R1/6, marked by the expression of Bar (white). (E, E′) Hdc expression (red in (E) and white in (E′)) is increased in <i>Tsc1<sup>Q600X</sup></i> mutant clones. (F, F′) Close up of boxed region in (E) showing that Hdc expression (red) is increased in the <i>Tsc1<sup>Q600X</sup></i> mutant clone behind the differentiation front for R1/6, marked by the expression of Bar (white). White lines mark clone outlines. (G, G′) Hdc expression (red) is decreased in a <i>Rheb<sup>2D1</sup></i> mutant clone (arrow). Mutant clones are marked by loss of GFP expression (green). Anterior is to the left. (H–K) Quantification of expression levels in mutant clones versus adjacent wild-type tissue in posterior clones. Data are represented as mean +/− SEM, **p≤0.01,***p≤0.001.</p>", "links"=>[], "tags"=>["insulin receptor", "differentiation phenotypes", "spatiotemporal control", "differentiation phenotype", "Hdc expression", "Unk forms", "unk acts", "Drosophila melanogaster eye", "Tsc 1.", "mTOR kinase", "transcriptional targets", "inr", "neurogenic components", "Negatively Regulated", "Growth Control Neuronal differentiation", "Growth control", "photoreceptor neurons", "pathway", "photoreceptor differentiation", "neurogenic role", "mouse retina", "gene headcase", "Uncouples Neuronal Differentiation", "system development", "energy levels", "neurogenesis cause"], "article_id"=>1168324, "categories"=>["Uncategorised"], "users"=>["Amélie Avet-Rochex", "Nancy Carvajal", "Christina P. Christoforou", "Kelvin Yeung", "Katja T. Maierbrugger", "Carl Hobbs", "Giovanna Lalli", "Umut Cagin", "Cedric Plachot", "Helen McNeill", "Joseph M. Bateman"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004624.g005", "stats"=>{"downloads"=>1, "page_views"=>25, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hdc_expression_is_controlled_by_InR_mTOR_signalling_and_unk_/1168324", "title"=>"Hdc expression is controlled by InR/mTOR signalling and <i>unk</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:59:05"}

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Relative Metric

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