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Multiple loci have been associated with HPE in humans, and potential causative genes at 14 of these loci have been identified. Although <jats:italic>TGIF1<\/jats:italic> (originally TGIF, for Thymine Guanine\u2010Interacting Factor) is among the most frequently screened genes in HPE patients, an understanding of how mutations in this gene contribute to the pathogenesis of HPE has remained elusive. However, mouse models based on loss of function of <jats:italic>Tgif1<\/jats:italic>, and the related <jats:italic>Tgif2<\/jats:italic> gene, have shed some light on how human <jats:italic>TGIF1<\/jats:italic> variants might cause HPE. Functional analyses of TGIF proteins and of <jats:italic>TGIF1<\/jats:italic> single nucleotide variants from HPE patients, combined with analysis of forebrain development in mouse embryos lacking both <jats:italic>Tgif1<\/jats:italic> and <jats:italic>Tgif2<\/jats:italic>, suggest that TGIFs regulate the transforming growth factor \u00df\/Nodal signaling pathway and sonic hedgehog (SHH) signaling independently. Although, some developmental processes that are regulated by TGIFs may be Nodal\u2010dependent, it appears that the forebrain patterning defects and HPE in <jats:italic>Tgif<\/jats:italic> mutant mouse embryos is primarily due to altered signaling via the Shh pathway.<\/jats:p>","DOI":"10.1002\/ajmg.c.31612","type":"journal-article","created":{"date-parts":[[2018,5,11]],"date-time":"2018-05-11T12:22:53Z","timestamp":1526041373000},"page":"128-139","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Functions of TGIF homeodomain proteins and their roles in normal brain development and holoprosencephaly"],"prefix":"10.1002","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4652-5350","authenticated-orcid":false,"given":"David","family":"Wotton","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Center for Cell Signaling University of Virginia Charlottesville Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichiro","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology University of Michigan Medical School Ann Arbor Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,11]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00527-16"},{"issue":"21","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"4975","DOI":"10.1242\/dev.129.21.4975","article-title":"Chordin and noggin promote organizing centers of forebrain development in the mouse","volume":"129","author":"Anderson R. 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