{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T08:23:49Z","timestamp":1787819029043,"version":"build-2784847793"},"reference-count":48,"publisher":"The Company of Biologists","issue":"3","license":[{"start":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:00:00Z","timestamp":1675382400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"name":"Department of Biotechnology, Government of India","award":["BT\/PR23629\/MED\/97\/376\/2017"],"award-info":[{"award-number":["BT\/PR23629\/MED\/97\/376\/2017"]}]},{"name":"Ministry of Human Resources and Development, Government of India"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>During embryonic development, the forebrain roof plate undergoes invagination, leading to separation of the cerebral hemispheres. Any defects in this process, in humans, lead to middle interhemispheric holoprosencephaly (MIH-HPE). In this study, we have identified a previously unreported downstream mediator of retinoic acid (RA) signaling, CNKSR2, which is expressed in the forebrain roof plate in the chick embryo. Knockdown of CNKSR2 affects invagination, cell proliferation and patterning of the roof plate, similar to the phenotypes observed upon inhibition of RA signaling. We further demonstrate that CNKSR2 functions by modulating the Ras\/Raf\/MEK signaling. This appears to be crucial for patterning of the forebrain roof plate and its subsequent invagination, leading to the formation of the cerebral hemispheres. Thus, a set of novel molecular players have been identified that regulate the morphogenesis of the avian forebrain.<\/jats:p>","DOI":"10.1242\/dev.200857","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T10:08:01Z","timestamp":1675418881000},"source":"Crossref","is-referenced-by-count":6,"title":["<i>CNKSR2<\/i>, a downstream mediator of retinoic acid signaling, modulates the Ras\/Raf\/MEK pathway to regulate patterning and invagination of the chick forebrain roof plate"],"prefix":"10.1242","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0709-1473","authenticated-orcid":false,"given":"Niveda","family":"Udaykumar","sequence":"first","affiliation":[{"name":"Indian Institute of Technology Kanpur 1 Department of Biological Sciences and Bioengineering , , Kanpur 208016 Uttar Pradesh , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd Ali Abbas","family":"Zaidi","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology Kanpur 1 Department of Biological Sciences and Bioengineering , , Kanpur 208016 Uttar Pradesh , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishwarya","family":"Rai","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology Kanpur 1 Department of Biological Sciences and Bioengineering , , Kanpur 208016 Uttar Pradesh , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7316-6376","authenticated-orcid":false,"given":"Jonaki","family":"Sen","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology Kanpur 1 Department of Biological Sciences and Bioengineering , , Kanpur 208016 Uttar Pradesh , India"},{"name":"Mehta Family Center for Engineering in Medicine (MFCEM), Indian Institute of Technology Kanpur 2 , Kanpur 208016, Uttar Pradesh , India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"2023020310075840400_DEV200857C1","doi-asserted-by":"publisher","first-page":"3081","DOI":"10.1242\/dev.128.16.3081","article-title":"The zebrafish neckless mutation reveals a requirement for raldh2 in mesodermal signals that pattern the hindbrain","volume":"128","author":"Begemann","year":"2001","journal-title":"Development"},{"key":"2023020310075840400_DEV200857C2","first-page":"532","article-title":"Retinoic acid differentially regulates cancer cell proliferation via dose-dependent modulation of the mitogen-activated protein kinase pathway","volume":"1","author":"Crowe","year":"2003","journal-title":"Mol. Cancer Res."},{"key":"2023020310075840400_DEV200857C3","doi-asserted-by":"publisher","first-page":"e40","DOI":"10.1111\/epi.13666","article-title":"Frequency of CNKSR2 mutation in the X-linked epilepsy-aphasia spectrum","volume":"58","author":"Damiano","year":"2017","journal-title":"Epilepsia"},{"key":"2023020310075840400_DEV200857C4","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s12881-020-01004-2","article-title":"Exons deletion of CNKSR2 gene identified in X-linked syndromic intellectual disability","volume":"21","author":"Daoqi","year":"2020","journal-title":"BMC Med. Genet."},{"key":"2023020310075840400_DEV200857C5","doi-asserted-by":"publisher","first-page":"11343","DOI":"10.1073\/pnas.0502933102","article-title":"Control of the segmentation process by graded MAPK\/ERK activation in the chick embryo","volume":"102","author":"Delfini","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023020310075840400_DEV200857C6","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/1750-1172-2-8","article-title":"Holoprosencephaly","volume":"2","author":"Dubourg","year":"2007","journal-title":"Orphanet J. Rare Dis."},{"key":"2023020310075840400_DEV200857C7","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1093\/hmg\/ddq556","article-title":"NOTCH, a new signaling pathway implicated in holoprosencephaly","volume":"20","author":"Dupe","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"2023020310075840400_DEV200857C8","doi-asserted-by":"publisher","first-page":"9633","DOI":"10.1523\/JNEUROSCI.0650-21.2021","article-title":"Cnksr2 loss in mice leads to increased neural activity and behavioral phenotypes of epilepsy-aphasia syndrome","volume":"41","author":"Erata","year":"2021","journal-title":"J. Neurosci."},{"key":"2023020310075840400_DEV200857C9","doi-asserted-by":"publisher","first-page":"2203","DOI":"10.1242\/dev.124.11.2203","article-title":"Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development","volume":"124","author":"Furuta","year":"1997","journal-title":"Development"},{"key":"2023020310075840400_DEV200857C10","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1172\/JCI38937","article-title":"Pathogenesis of holoprosencephaly","volume":"119","author":"Geng","year":"2009","journal-title":"J. Clin. Investig."},{"key":"2023020310075840400_DEV200857C11","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1093\/hmg\/ddm328","article-title":"Zebrafish model of holoprosencephaly demonstrates a key role for TGIF in regulating retinoic acid metabolism","volume":"17","author":"Gongal","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"2023020310075840400_DEV200857C12","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1016\/j.bbadis.2010.09.005","article-title":"Aberrant forebrain signaling during early development underlies the generation of holoprosencephaly and coloboma","volume":"1812","author":"Gongal","year":"2011","journal-title":"Biochim. Biophys. (BBA) \u2013 Mol. Basis Dis."},{"key":"2023020310075840400_DEV200857C13","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1242\/dev.122390","article-title":"Retinoic acid signaling regulates development of the dorsal forebrain midline and the choroid plexus in the chick","volume":"142","author":"Gupta","year":"2015","journal-title":"Development"},{"key":"2023020310075840400_DEV200857C14","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1007\/978-94-011-6621-8_21","article-title":"Pigs born without eye balls","volume-title":"Problems of birth defects","author":"Hale","year":"1933"},{"key":"2023020310075840400_DEV200857C15","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.ydbio.2006.11.021","article-title":"Retinoids control anterior and dorsal properties in the developing forebrain","volume":"303","author":"Halilagic","year":"2007","journal-title":"Dev. Biol."},{"key":"2023020310075840400_DEV200857C16","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1002\/jmor.1050880104","article-title":"A series of normal stages in the development of the chick embryo","volume":"88","author":"Hamburger","year":"1951","journal-title":"J. Morphol."},{"key":"2023020310075840400_DEV200857C17","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1186\/s12920-021-01033-7","article-title":"CNKSR2-related neurodevelopmental and epilepsy disorder: a cohort of 13 new families and literature review indicating a predominance of loss of function pathogenic variants","volume":"14","author":"Higa","year":"2021","journal-title":"BMC Med. Genomics"},{"key":"2023020310075840400_DEV200857C18","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1159\/000335159","article-title":"Loss-of-function CNKSR2 mutation is a likely cause of non-syndromic X-linked intellectual disability","volume":"2","author":"Houge","year":"2011","journal-title":"Mol. Syndromol."},{"key":"2023020310075840400_DEV200857C19","doi-asserted-by":"publisher","first-page":"2140","DOI":"10.1038\/s41598-018-20242-2","article-title":"Link between the causative genes of holoprosencephaly: Zic2 directly regulates Tgif1 expression","volume":"8","author":"Ishiguro","year":"2018","journal-title":"Sci. Rep."},{"key":"2023020310075840400_DEV200857C20","doi-asserted-by":"publisher","first-page":"101427","DOI":"10.1016\/j.jbc.2021.101427","article-title":"The synaptic scaffolding protein CNKSR2 interacts with CYTH2 to mediate hippocampal granule cell development","volume":"297","author":"Ito","year":"2021","journal-title":"J. Biol. Chem."},{"key":"2023020310075840400_DEV200857C21","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1159\/000328203","article-title":"TGIF mutations in human holoprosencephaly: correlation between genotype and phenotype","volume":"1","author":"Keaton","year":"2010","journal-title":"Mol. Syndromol."},{"key":"2023020310075840400_DEV200857C22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1017\/S1462399407000440","article-title":"Holoprosencephaly: new models, new insights","volume":"9","author":"Krauss","year":"2007","journal-title":"Expert Rev. Mol. Med."},{"key":"2023020310075840400_DEV200857C23","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1242\/dev.127.3.457","article-title":"A local Wnt-3a signal is required for development of the mammalian hippocampus","volume":"127","author":"Lee","year":"2000","journal-title":"Development"},{"key":"2023020310075840400_DEV200857C24","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/S0960-9822(02)00509-2","article-title":"Vitamin A-deficient quail embryos have half a hindbrain and other neural defects","volume":"6","author":"Maden","year":"1996","journal-title":"Curr. Biol."},{"key":"2023020310075840400_DEV200857C25","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.ydbio.2005.07.015","article-title":"Dynamic and sequential patterning of the zebrafish posterior hindbrain by retinoic acid","volume":"285","author":"Maves","year":"2005","journal-title":"Dev. Biol."},{"key":"2023020310075840400_DEV200857C26","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1002\/dvdy.20128","article-title":"Raldh2 expression in optic vesicle generates a retinoic acid signal needed for invagination of retina during optic cup formation","volume":"231","author":"Mic","year":"2004","journal-title":"Dev. Dyn."},{"key":"2023020310075840400_DEV200857C27","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1016\/j.ydbio.2006.11.035","article-title":"Role of retinoic acid during forebrain development begins late when Raldh3 generates retinoic acid in the ventral subventricular zone","volume":"303","author":"Molotkova","year":"2007","journal-title":"Dev. Biol."},{"key":"2023020310075840400_DEV200857C28","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1002\/mc.10150","article-title":"Cell growth inhibition by all-trans retinoic acid in SKBR-3 breast cancer cells: involvement of protein kinase C? And extracellular signal-regulated kinase mitogen-activated protein kinase","volume":"38","author":"Nakagawa","year":"2003","journal-title":"Mol. Carcinog."},{"key":"2023020310075840400_DEV200857C29","doi-asserted-by":"publisher","first-page":"2479","DOI":"10.1093\/hmg\/8.13.2479","article-title":"The mutational spectrum of the Sonic Hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly","volume":"8","author":"Nanni","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"2023020310075840400_DEV200857C30","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.neuron.2003.08.006","article-title":"A requirement for retinoic acid-mediated transcriptional activation in ventral neural patterning and motor neuron specification","volume":"40","author":"Novitch","year":"2003","journal-title":"Neuron"},{"key":"2023020310075840400_DEV200857C31","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1002\/wdev.161","article-title":"Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans","volume":"4","author":"Petryk","year":"2015","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"2023020310075840400_DEV200857C32","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0248-4900(01)01125-X","article-title":"The Raf\/MEK\/ERK pathway: new concepts of activation","volume":"93","author":"Peyssonnaux","year":"2001","journal-title":"Biol. Cell"},{"key":"2023020310075840400_DEV200857C33","doi-asserted-by":"publisher","first-page":"e00861","DOI":"10.1002\/mgg3.861","article-title":"A de novo variant in the X\u2013linked gene CNKSR2 is associated with seizures and mild intellectual disability in a female patient","volume":"7","author":"Polla","year":"2019","journal-title":"Mol. Genet. Genomic Med."},{"key":"2023020310075840400_DEV200857C34","doi-asserted-by":"publisher","first-page":"2577","DOI":"10.1002\/ajmg.a.31377","article-title":"SIX3 mutations with holoprosencephaly","volume":"140A","author":"Ribeiro","year":"2006","journal-title":"Am. J. Med. Genet. A"},{"key":"2023020310075840400_DEV200857C35","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1242\/dev.02204","article-title":"Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling","volume":"133","author":"Ribes","year":"2006","journal-title":"Development"},{"key":"2023020310075840400_DEV200857C36","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/S0092-8674(00)80226-3","article-title":"Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by ras","volume":"89","author":"Rodriguez-Viciana","year":"1997","journal-title":"Cell"},{"key":"2023020310075840400_DEV200857C37","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1002\/ajmg.c.30236","article-title":"The molecular genetics of holoprosencephaly","volume":"154C","author":"Roessler","year":"2010","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2023020310075840400_DEV200857C38","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1101\/gad.5.8.1333","article-title":"Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis","volume":"5","author":"Rossant","year":"1991","journal-title":"Genes Dev."},{"key":"2023020310075840400_DEV200857C39","doi-asserted-by":"publisher","first-page":"e63670","DOI":"10.1371\/journal.pone.0063670","article-title":"A genome-wide screen indicates correlation between differentiation and expression of metabolism related genes","volume":"8","author":"Roy","year":"2013","journal-title":"PLoS One"},{"key":"2023020310075840400_DEV200857C40","doi-asserted-by":"publisher","first-page":"dev175729","DOI":"10.1242\/dev.175729","article-title":"MicroRNA-19b restricts Wnt7b to the hem, which induces aspects of hippocampus development in the avian forebrain","volume":"146","author":"Sindhu","year":"2019","journal-title":"Development"},{"key":"2023020310075840400_DEV200857C41","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/nature08298","article-title":"The avian Z-linked gene DMRT1 is required for male sex determination in the chicken","volume":"461","author":"Smith","year":"2009","journal-title":"Nature"},{"key":"2023020310075840400_DEV200857C42","doi-asserted-by":"publisher","first-page":"570","DOI":"10.12998\/wjcc.v6.i12.570","article-title":"CNKSR2 mutation causes the X-linked epilepsy-aphasia syndrome: a case report and review of literature","volume":"6","author":"Sun","year":"2018","journal-title":"World J. Clin. Cases"},{"key":"2023020310075840400_DEV200857C43","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/0092-8674(95)90205-8","article-title":"The C. elegans ksr-1 gene encodes a novel raf-related kinase involved in Ras-mediated signal transduction","volume":"83","author":"Sundaram","year":"1995","journal-title":"Cell"},{"key":"2023020310075840400_DEV200857C44","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/S0092-8674(00)81766-3","article-title":"CNK, a RAF-binding multidomain protein required for RAS signaling","volume":"95","author":"Therrien","year":"1998","journal-title":"Cell"},{"key":"2023020310075840400_DEV200857C45","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1002\/cne.21368","article-title":"Molecular heterogeneity of developing retinal ganglion and amacrine cells revealed through single cell gene expression profiling","volume":"502","author":"Trimarchi","year":"2007","journal-title":"J. Comp. Neurol."},{"key":"2023020310075840400_DEV200857C46","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1002\/ana.24274","article-title":"Absent CNKSR2 causes seizures and intellectual, attention, and language deficits","volume":"76","author":"Vaags","year":"2014","journal-title":"Ann. Neurol."},{"key":"2023020310075840400_DEV200857C47","doi-asserted-by":"publisher","first-page":"4375","DOI":"10.1074\/jbc.M708471200","article-title":"A MAPK-positive feedback mechanism for BLR1 signaling propels retinoic acid-triggered differentiation and cell cycle arrest","volume":"283","author":"Wang","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2023020310075840400_DEV200857C48","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1038\/gim.2017.68","article-title":"In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics","volume":"20","author":"Weiss","year":"2018","journal-title":"Genet. Med."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.200857\/2467660\/dev200857.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.200857\/2467660\/dev200857.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T10:08:11Z","timestamp":1675418891000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/150\/3\/dev200857\/286897\/CNKSR2-a-downstream-mediator-of-retinoic-acid"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,3]]},"references-count":48,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,2,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.200857","relation":{},"ISSN":["0950-1991","1477-9129"],"issn-type":[{"value":"0950-1991","type":"print"},{"value":"1477-9129","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,3]]},"article-number":"dev200857"}}