Faculty Collaboration Database

Genetic and Molecular Analyses indicate independent effects of TGIFs on Nodal and Gli3 in neural tube patterning. Eur J Hum Genet 2017 Feb;25(2):208-215

Date

12/08/2016

Pubmed ID

27924807

Pubmed Central ID

PMC5255961

DOI

10.1038/ejhg.2016.164

Scopus ID

2-s2.0-85001838144 (requires institutional sign-in at Scopus site)   15 Citations

Abstract

Holoprosencephaly (HPE) is a prevalent craniofacial developmental disorder that has both genetic and environmental causes. The gene encoding TG-interacting factor 1 (TGIF1) is among those that are routinely screened in HPE patients. However, the mechanisms by which TGIF1 variants cause HPE are not fully understood. TGIF1 is a transcriptional repressor that limits the output of the Transforming Growth Factor ß (TGFß)/Nodal signaling pathway, and HPE in patients with TGIF1 variants has been suggested to be due to increased Nodal signaling. Mice lacking both Tgif1 and its paralog, Tgif2, have HPE, and embryos lacking Tgif function do not survive past mid-gestation. Here, we show that in the presence of a Nodal heterozygous mutation, proliferation defects are rescued and a proportion of embryos lacking all Tgif function survive to late gestation. However, these embryos have a classic HPE phenotype, suggesting that this is a Nodal-independent effect of Tgif loss of function. Further, we show that the Gli3 gene is a direct target for repression by Tgifs, independent of TGFß/Nodal signaling, consistent with Tgif mutations causing HPE via Nodal-independent effects on the Sonic Hedgehog (Shh) pathway. Based on this work, we propose a model for distinct functions of Tgifs in the Nodal and Shh/Gli3 pathways during forebrain development.

Author List

Taniguchi K, Anderson AE, Melhuish TA, Carlton AL, Manukyan A, Sutherland AE, Wotton D

Author

Kenichiro Taniguchi PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Line, Tumor
Cells, Cultured
Hedgehog Proteins
Holoprosencephaly
Homeodomain Proteins
Humans
Kruppel-Like Transcription Factors
Mice
Mice, Inbred C57BL
Mutation
Nerve Tissue Proteins
Neural Tube
Nodal Protein
Repressor Proteins
Signal Transduction
Zinc Finger Protein Gli3