TGIF, a gene associated with human brain defects, regulates neuronal development

Abstract

-TG-3 -interacting factor (TGIF) is an atypical homeodomain protein.In vitro studies have shown that TGIF can repress transcription mediated by either of two signaling pathways: TGF-␤ and retinoic acid signaling. Mutations in TGIF have been detected in patients with holoprosencephaly (HPE), a severe brain malformation associated with mental retardation. Thus, TGIF must play an essential role in nervous system development. However, the precise function of TGIF during vertebrate neural development is unknown. To investigate the in vivo role of TGIF, we overexpressed TGIF in the developing chick neural tube. Overexpressed TGIF decreased expression of specific genes expressed in dorsally restricted domains of the neural tube, including Cath1, Msx2, Pax6, and Wnt1. In contrast, the expression of other transcription factors, including those necessary for ventral fate such as Nkx2.2, was not affected. Furthermore, a missense mutation in TGIF identified in an HPE patient disrupted the activity of TGIF. In addition, the related protein TGIF2 did not demonstrate the same activity as TGIF. Our data suggest that TGIF plays an important role in regulating the expression of genes expressed in specific dorsal-ventral domains during neural development.

Insights into the organization of dorsal spinal cord pathways from an evolutionarily conserved raldh2 intronic enhancer

“…dI1), restricting raldh2 expression to the RP and dI1 (Fig. 9) (Wine-Lee et al, 2004;Zhou et al, 2003;Iulianella et al, 2003;Knepper et al, 2006;Sheng et al, 1997).…”

“…These sites display matrix identities to the matrix core that range between 86 and 90% and are conserved across amphibian, avian, marsupial, rodent and primate enhancers. Site D2 contains another, overlapping Tcfhomeodomain binding site, this time for the repressor homeodomain transcription factor 5Ј-TG-3Ј interacting factor (Tgif; also known as TGFB-induced factor homeobox 1) (Knepper et al, 2006). These binding sites display matrix identities of 90% and are conserved in amphibian, avian, marsupial, rodent and primate enhancers.…”

Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars

“…The TGF-␤ signaling pathway is associated with many different early developmental processes (16), but disruptions of its function have also been detected in several adult disease states (17). Other genes included in the GAD 67 regulatory network include CNNTB1 or ␤-catenin, GSK-3␤, and LEF1, three key components of the Wnt signaling pathway.…”

TGFB-induced factor (TGIF): a candidate gene for psychosis on chromosome 18p

“…The three sources of information (DIGS, FIGS and available records) were analyzed by bilingual psychiatrists to obtain a lifetime consensus diagnosis for each affected subject, using a process of best estimation described in previous studies of the CVCR. [10][11][12][13][14][15][16] A consensus diagnosis of lifetime history of psychosis was also arrived at, utilizing the methodology described in Escamilla et al 17 Assessors and best estimate teams were the same for Samples 1 and 2, and there was no change in protocol, as Sample 2 was technically the next group of families recruited after Sample 1.…”

“…TGIF is a member of the three-amino-acid loop extension (TALE) superclass of homeobox proteins and acts as an inhibitory transcription factor by repressing transcription of several genes. TGIF regulates normal neuronal development, neuron survival 14 and controls the expression of the dopamine receptors in neurons. 15 Based on our results we propose TGIF as a candidate gene for psychosis on Ch18p11.3.…”