2010 Annual Report - Institute for Molecular Bioscience - University ...

imb annual report 2010
40
DAGMAR WILHELM
TOWARDS A NEW UNDERSTANDING OF THE
REPRODUCTIVE SYSTEM: FROM NON-CODING
RNAS TO DISEASE
OUR GROUP FOCUSES ON THE
elucidation of regulatory mechanisms
that control gene expression during
embryonic development. One of the
most amazing biological processes is
the development of a fertilised egg into
a complex organism. It involves the
orchestration of cellular processes such as
cell proliferation, migration, differentiation
and apoptosis, which is controlled by a
delicate network of gene regulation and
interaction. Disturbance of this network
by gene mutation or misexpression during
development results in malformation and
malfunction of organs, diseases such as
cancer, and often lethality. Therefore, each
of these processes must involve a large
number of regulatory mechanisms.
Until recently our work centred around the
conventional dogma, which states that
gene activity is controlled by transcription
factor binding to proximal promoters and/
or enhancers adjacent to genes. We are
now extending these studies to include
the fact that gene activity is also regulated
post-transcriptionally by non-coding RNAs
(ncRNAs), such as microRNAs. In addition
to investigating the role of microRNAs
during development, we have discovered
a new class of ncRNAs, uaRNAs (3’UTRassociated
non-coding RNAs), that displays
a highly regulated stage- and sex-specific
expression pattern during embryogenesis.
Furthermore, we want to use the
knowledge of small RNA processing and
function, also called RNA interference
(RNAi), as a tool to control pest species in
Australia. The common carp represents an
increasing menace to Australian freshwater
ecosystems. Further unchecked growth
and spread of the carp population poses
a threat to many native fish species. In this
project we are investigating the biology of
RNAi in carp and zebrafish, to investigate
the potential of a “daughterless” approach
by making use of the endogenous RNAi
processing machinery to knock down
aromatase and thereby control carp
numbers.
Our research uses mouse and zebrafish
as model systems and integrates
molecular and developmental biology to
study mechanisms of gene regulation
by transcription factors as well as
ncRNAs during embryonic development,
concentrating on sex determination and
gonad development but extending to
other developmental systems such as
chondrogenesis.
The aims of our research are to address
the intersections of the following questions:
1 What are the regulatory mechanisms
underlying the development of the
ovary
2 What are the roles of ncRNAs, including
long and small RNAs, during the
development of testes and ovaries
3 What are the mechanisms of
processing and function of small RNAs
in fish
RESEARCH PROJECTS
• Characterisation of the role of miR-
202 and miR-140 during embryonic
development
• Analysis of novel microRNAs involved in
gonad development
• Functional characterisation of ncRNAs
during embryonic development
• Studying the cellular and molecular
regulation of foetal ovary development
• Characterisation of RNAi in fish
KEY PUBLICATIONS
Mercer, T.R.*, Wilhelm, D.*, Dinger, M.E.*,
Solda, G.*, Korbie, D.J., Glazov, E.A.,
Truong, V., Schwenke, M., Matthaei, K.I.,
Saint, R., Koopman, P., and Mattick, J.S.
(2010). Expression of distinct RNAs from
3’ untranslated regions. Nucleic Acids
Research Epub November 12.
McFarlane, L., and Wilhelm, D. (2009).
Non-coding RNA in mammalian sexual
development. Sexual Development 3:
302-316.
Wilhelm, D., Hiramatsu, R., Mizusaki,
H., Widjaja, L., Combes, A.N., Kanai,
Y., and Koopman, P. (2007). SOX9
regulates prostaglandin D synthase
gene transcription in vivo to ensure
testis development. Journal of Biological
Chemistry 282: 10553-10560.
Wilhelm, D., Palmer, S., and Koopman,
P. (2007). Sex determination and gonadal
development in mammals. Physiological
Reviews 87: 1-28.
Wilhelm, D., Martinson, F., Bradford, S.,
Wilson, M.J., Combes, A., Beverdam, A.,
Bowles, J., Mizusaki, H., and Koopman,
P. (2005). Sertoli cell differentiation is
induced both cell-autonomously and
through prostaglandin signalling to
activate Sox9 during mammalian sex
determination. Developmental Biology
287: 111-124.
Wilhelm, D., and Englert, C. (2002). The
Wilms tumour suppressor WT1 regulates
gonadal development by activation of Sf1.
Genes and Development 16: 1839-1851.
LAB MEMBERS
Research Officer: Dr James Palmer
Research Assistants: Vy Truong, Huijun
Chen, Emmanuelle Frampton
PhD Students: Lindsey McFarlane, Elanor
Wainwright
Occupational Trainee: Nicolas Melin
Honours Student: Joanna Rakoczy