title: Zic-associated holoprosencephaly: zebrafish Zic1 controls midline formation and forebrain patterning by regulating Nodal, Hedgehog, and retinoic acid signaling.
abstract: Holoprosencephaly (HPE) is the most frequently observed human embryonic forebrain defect. Recent evidence indicates that the two major forms of HPE, classic HPE and midline interhemispheric (MIH) HPE, are elicited by two different mechanisms. The only gene known to be associated with both forms of HPE is Zic2. We used the zebrafish Danio rerio as a model system to study Zic knockdown during midline formation by looking at the close homolog Zic1, which is expressed in an overlapping fashion with Zic2. Zic1 knockdown in zebrafish leads to a strong midline defect including partial cyclopia due to attenuated Nodal and Hedgehog signaling in the anterior ventral diencephalon. Strikingly, we were able to show that Zic1 is also required for maintaining early forebrain expression of the retinoic acid (RA)-degrading enzyme cyp26a1. Zic1 LOF leads to increased RA levels in the forebrain, subsequent ventralization of the optic vesicle and down-regulation of genes involved in dorsal BMP signaling. Repression of BMP signaling in dorsal forebrain has been implicated in causing MIH HPE. This work provides a mechanistical explanation at the molecular level of why Zic factors are associated with both major forms of HPE.
authors.affiliation: Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Maurus
authors.forename: William A
authors.initials: WA
authors.lastname: Harris
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004027:Diencephalon / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D053823:Hedgehog Proteins / Q000378:metabolism; D016142:Holoprosencephaly / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D055456:Nodal Signaling Ligands / Q000378:metabolism; D016548:Prosencephalon / Q000196:embryology; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism; D015854:Up-Regulation; D015027:Zebrafish / Q000196:embryology* / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D055456:Nodal Signaling Ligands; D014157:Transcription Factors; D029961:Zebrafish Proteins; C512832:ndr2 protein, zebrafish; C492121:zic1 protein, zebrafish; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; C000607085:cyp26a1 protein, zebrafish