title: Six3 regulates optic nerve development via multiple mechanisms.
abstract: Malformations of the optic nerve lead to reduced vision or even blindness. During optic nerve development, retinal ganglion cell (RGC) axons navigate across the retina, exit the eye to the optic stalk (OS), and cross the diencephalon midline at the optic chiasm en route to their brain targets. Many signalling molecules have been implicated in guiding various steps of optic nerve pathfinding, however much less is known about transcription factors regulating this process. Here we show that in zebrafish, reduced function of transcription factor Six3 results in optic nerve hypoplasia and a wide repertoire of RGC axon pathfinding errors. These abnormalities are caused by multiple mechanisms, including abnormal eye and OS patterning and morphogenesis, abnormal expression of signalling molecules both in RGCs and in their environment and anatomical deficiency in the diencephalic preoptic area, where the optic chiasm normally forms. Our findings reveal new roles for Six3 in eye development and are consistent with known phenotypes of reduced SIX3 function in humans. Hence, the new zebrafish model for Six3 loss of function furthers our understanding of the mechanisms governing optic nerve development and Six3-mediated eye and forebrain malformations.
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Samuel
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Ariel M
authors.initials: AM
authors.lastname: Rubinstein
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Tehila T
authors.initials: TT
authors.lastname: Azar
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Ben-Moshe Livne
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Seok-Hyung
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Inbal
mesh_terms: D000818:Animals; D005124:Eye Abnormalities / Q000196:embryology / Q000235:genetics; D005136:Eye Proteins / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009897:Optic Chiasm / Q000166:cytology / Q000196:embryology*; D009901:Optic Nerve Diseases / Q000151:congenital / Q000196:embryology / Q000235:genetics; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D000097607:Homeobox Protein SIX3
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000097607:Homeobox Protein SIX3
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