Important Clue to
Understanding the Pathogenesis of Ciliary Disorders
26 July 2010Neuherberg, Germany
A research
team led by Dr. Heiko Lickert of Helmholtz
Zentrum München has pinpointed a gene that
is essential for the physiologically correct
disassembly of cilia. Errors in the
regulation of cilia assembly are implicated
in a variety of human syndromes. Until now,
however, the consequences of faulty cilia
disassembly have not yet been elucidated.
The findings are reported in the current
issue of the prestigious journal
Developmental Cell.
Scientists
led by Dr. Heiko Lickert, research group
leader at the Institute of Stem Cell
Research of Helmholtz Zentrum München, have
identified the first gene shown to regulate
cilia disassembly in a living organism. If
the gene is defective, double and forked
cilia develop – thus the name Pitchfork. The
consequences of the mutation include typical
defects in the left-right asymmetry of body
organs and heart failure.
The functional
investigations were conducted
primarily on the mouse model,
together with the Institute of
Developmental Genetics and the
Department of Protein Analytics of
Helmholtz Zentrum München. However,
Dr. Lickert and his collaboration
partner Nicolas Katsanis of Duke
University in the U.S. were also
able to show mutations in the
Pitchfork gene in patients with
ciliary diseases. In humans, the
substitution of merely one amino
acid in the Pitchfork protein can
lead to an inversed position of all
internal organs (situs inversus), to
kidney and liver diseases, but also
to severe heart defects. “Our study”
Dr. Lickert said, “provides a new
entry point to understand and
categorize ciliary disease.”
Cilia are hair-like cell
protuberances, 5 to 10 µm long and
250 nm thick, which are present in
almost all human or animal cells.
They function like antennas in the
cells and play a pivotal role in the
perception of the cellular
surroundings and signal
transduction.
Defective cilia usually have genetic
causes and severe consequences: In
recent years more than 30 diseases
could be traced to ciliary
dysfunctions. These ciliopathies
affect numerous organ systems and
show diverse clinical symptoms, but
the molecular and cellular basis for
this is not yet understood. The
resulting disorders include
developmental defects such as
polycystic kidney, liver and
pancreas diseases (incidence 1:800)
and also heart defects and
adiposity. An increased risk for
common diseases such as diabetes or
cancer is also very probable.
Despite the far-reaching
significance of cilia, many aspects
of the biology of these organelles
are not yet known and many questions
remain to be answered. These include
the regulation of the body’s own
processes (homeostasis), signal
transduction between cells, organ
and embryonic development, and the
assembly and disassembly of cilia in
the different phases of the cell
cycle.
Further Information:
Original
Publication: Kinzel D. et al.:
Pitchfork regulates primary cilia
disassembly and left-right
asymmetry. Developmental Cell 2010;
Developmental Cell 19(1) pp. 66 - 77
(pdf
download).
Helmholtz Zentrum
München
is the German Research Center for Environmental
Health. Our aim is to develop an individualized
medical approach to the prevention and treatment of
widespread common diseases such as diabetes
mellitus, lung diseases and diseases of the nervous
system. As one of the world’s leading centers with a
focus on Environmental Health, we investigate the
interaction of genetic disposition, environmental
factors and lifestyle. Helmholtz Zentrum München has
approximately 1800 staff members; its head office is
located in Neuherberg to the north of Munich on a
50-hectare research campus. Helmholtz Zentrum
München belongs to the Helmholtz Association,
Germany’s largest research organization, a community
of 16 scientific-technical and medical-biological
research centers with a total of 26,500 staff
members. – www.helmholtz-muenchen.de
The Institute of Stem Cell
Research investigates
the main regulatory elements of cell fate and cell
proliferation in different organ systems. The
scientists study stem cells of different organs, for
instance of the nervous system or the hematapoietic
system, to elucidate the molecular and cellular
mechanisms responsible for the key characteristic
common to all stem cells. Another main focus is the
regulation of the generation of specific cell types
from stem cells with respect to a reconstituting
therapeutic approach - www.helmholtz-muenchen.de/isf
Contact for Media Representatives
Sven Winkler, Helmholtz
Zentrum München – German Research Center for
Environmental Health, Ingolstädter Landstr. 1, 85764
Neuherberg, Germany - Phone: +49(0)89-3187-3946, Fax
+49(0)89-3187-3324, Internet: www.helmholtz-muenchen.de,
e-mail: presse@helmholtz-muenchen.de.
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