David Wotton, Ph.D.
Professor of Biochemistry
and Molecular Genetics
Regulation by TGFb Signaling
and the Role of Transcriptional Corepressors
The gene responses
activated by TGF beta family signaling underlie many developmental and
proliferative events, including mesoderm induction, antiproliferative
responses in mammalian cells and dorsalization in fly embryos.
Mutations in components of the signal transduction pathway, resulting
in a loss of TGF beta signaling can contribute to human cancer. From
work with targeted disruptions in mice, it is clear that alterations in
TGF beta signaling can result in severe developmental defects.
TGF beta family ligands
bind to specific cell surface receptor serine/threonine kinases,
resulting in receptor multimerization and activation. The response to
TGF beta family ligands is dependent on the intracellular mediators of
TGF beta signaling, the Smad proteins. Following TGF beta
receptor-mediated phosphorylation and activation of pathway-specific
Smad proteins, the activated Smad complexes move to the nucleus where
they activate gene expression.
Smads and TGIF:
regulation by Smads is dependent on interactions with transcriptional
coactivators and corepressors, including the homeodomain protein TGIF.
Interaction of Smad proteins with TGIF precludes interaction with
coactivators resulting in repression of transcription. TGIF can
interact with several general corepressor, including histone
deacetylases (HDAC) and can recruit HDACs to an activated Smad complex.
The level of TGIF within the nucleus can thereby regulate the
transcriptional outcome of a TGF beta response. Signaling inputs that
regulate the level or activity of coactivators and corepressors with
which Smads interact are likely to alter the balance between
transcriptional activation and repression, thus modulating TGF
Transcriptional repression by TGIF:
TGIF has intrinsic
transcriptional repression functions, independent of TGF beta
signaling. TGIF represses transcription when bound directly to DNA via
its own homeodomain. Current work is aimed
at identifying components of TGIF-containing transcriptional repression
complexes and elucidating the role TGIF plays. We have demonstrated
that TGIF interacts with HDAC and CtBP, which may repress transcription
via interactions with polycomb group proteins. Thus, TGIF appears to
target general transcriptional corepressors to specific gene responses,
either via direct DNA binding, or by interaction with TGF
TGIF is a homeodomain transcription factor, of the
TALE superfamily. Members of this family of homeodomain proteins
generally bind DNA in association with other DNA binding proteins.
However, binding partners for TGIF are not yet known, and gene
responses regulated by TGIF independent of TGF beta signaling remain to
be identified. TGIF may play a role in regulating retinoid responsive
transcription and it will be of interest to clarify the role of TGIF in
this pathway and to identify other TGF beta-independent roles of TGIF.
We are currently attempting to identify both TGIF target genes and
other transcription factors with which TGIF interacts.
We have recently
demonstrated that the TGIF gene is mutated in holoprosencephaly (HPE),
a human genetic disorder affecting craniofacial development. The
primary defect in HPE is a failure of the brain to divide laterally.
Our aim is now to gain a better understanding of the role of TGIF
during development. Several components of the TGF beta signaling
pathway have been demonstrated to affect brain development and have
been implicated in HPE. The creation of specific mouse mutants
targeting different functions of TGIF will determine whether it is loss
of the TGF beta-dependent functions of TGIF that results in HPE and
generate a better understanding of the developmental roles of TGIF.
TGIF targets general corepressor complexes to
specific gene responses and appears to act in at least two separate
transcriptional regulatory pathways:
- Repressing TGF beta
activated gene expression via Smad interactions.
- Repressing a
distinct set of gene responses by direct DNA binding, and possibly via
interactions with other DNA binding proteins.
It is now important to
characterize DNA binding partners of TGIF and identify target genes. In
the long term we must also generate an understanding of how TGIF
regulates development and why loss of TGIF function results in HPE.