http://web.stanford.edu/group/brunet/Cell1999

Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor

The recent identification of the SMAD family of signal transducer proteins has unravelled the mechanisms by which transforming growth factor-beta (TGF-beta) signals from the cell membrane to the nucleus. Pathway-restricted SMADs are phosphorylated by specific cell-surface receptors that have serine/threonine kinase activity, then they oligomerize with the common mediator Smad4 and translocate to the nucleus where they direct transcription to effect the cell's response to TGF-beta. Inhibitory SMADs have been identified that block the activation of these pathway-restricted SMADs.

TGF-beta signalling from cell membrane to nucleus through SMAD proteins

Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity. Although studies of twins consistently indicate that a significant genetic component is involved, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.

/pdf/a-forkhead-domain-gene-is-mutated-in-a-severe-speech-and-2fz1xnf1xq.pdf

A forkhead-domain gene is mutated in a severe speech and language disorder

3 , accu- mulating large amounts of fat in their intestines and hypodermis Mutants in DAF-2 (a homologue of the mammalian insulin receptor) and AGE-1 (a homologue of the catalytic subunit of mammalian phosphatidylinositol 3-OH kinase) arrest develop- ment at the dauer stage 3  Moreover, animals bearing weak or temperature-sensitive mutations in daf-2 and age-1 can develop reproductively, but nevertheless show increased energy storage and longevity 1,2,4,5

/pdf/the-fork-head-transcription-factor-daf-16-transduces-insulin-1ik27vjand.pdf

The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans

To determine whether human X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome (IPEX; MIM 304930) is the genetic equivalent of the scurfy (sf) mouse, we sequenced the human ortholog (FOXP3) of the gene mutated in scurfy mice (Foxp3), in IPEX patients. We found four non-polymorphic mutations. Each mutation affects the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions.

X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.

Five years on the wings of fork head

DNA recognition site analysis of Xenopus wingedhelix proteins

The POU factor Oct-25 regulates the Xvent-2B gene and counteracts terminal differentiation in Xenopus embryos.

Transcription of the early response gene XFD-1' (XFKH1) in the dorsal lip (Spemann organizer) of Xenopus embryos is activated by dorsal mesoderm inducing factors. Promoter studies revealed the presence of an activin A response element (ARE) which is both necessary and sufficient for transcriptional activation of reporter genes in animal cap explants incubated with activin A. Surprisingly, this ARE is also active within vegetal explants in the absence of exogenously added inducers, but an additional inhibitory response element prevents transcription of the XFD-1' gene in the ventral/vegetal region of the embryo in vivo. This element is located upstream of the ARE, it responds to bone morphogenic proteins 2 and 4 (BMP-2/4) triggered signals and it overrides the activating properties of the ARE. Expression patterns of BMP-2 and BMP-4 in the late blastula stage embryo and, especially, their absence from the dorsal blastopore lip may thus control the spatial transcription of the XFD-1' gene. Accordingly, the temporal activation and the spatial restriction of XFD-1' gene activity to the Spemann organizer is regulated by antagonistic actions of two distinct members of the TGF-beta family (activin and BMP) which act on different promoter elements.

https://www.embopress.org/doi/pdf/10.1002/j.1460-2075.1996.tb01063.x

Antagonistic actions of activin A and BMP-2/4 control dorsal lip-specific activation of the early response gene XFD-1' in Xenopus laevis embryos.

Determination of GHB in urine and serum by LC/MS using a simple one-step derivative

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