Development
of new Drosophila models of Parkinson´s disease.
Parkinson’s
disease (PD) is the most common neurodegenerative
movement disorder. It is mainly characterized by the
loss of dopaminergic neurons in the substantia nigra
and, in some cases, by the formation of intracytoplasmatic
protein aggregates in those neurons (Lewy bodies). Although
PD is primarily a sporadic disorder, at least eleven
genes have been linked to the disease. This could be
the cause of the phenotypical heterogeneity of PD, and
suggests the existence of a variety of pathogenic routes
of the disease.
In
this context, we are currently working on several Drosophila
orthologs of the human PD genes, and other genes related
to them that could be potentially involved in the disease.
Our goal is to generate new models of PD in Drosophila.
Loss of function studies as well as transgenic approaches
to express the Drosophila and human genes in several
tissues are being performed in an effort to recapitulate
the pathological features of the disease. The ability
to perform facile genetic screens in Drosophila will
allow us to identify new genes that can modify the disease
phenotypes. With such studies we will be able to unravel
the molecular pathways involved in the pathogenesis
of PD..
Epithelial
planar cell polarity generation in Drosophila.
In
multicellular organisms epithelial cells are polarized
not only in the apical-basal axis, but also in the plane
of the epithelium. In vertebrates, this epithelial
planar cell polarization (PCP) is evident in
the regular appearance of fish scales and bird feathers,
and in internal organs such as the inner ear and oviduct,
where hairs and cilia are oriented precisely with respect
to each other. In invertebrates, PCP is evident in diverse
tissues. For example, in the Drosophila wing each cell
orients itself in the proximal-distal axis generating
a hair at the distal vertex. In the eye, PCP is manifest
in the regular ommatidial arrangement in the anterior-posterior
and dorsal-ventral axes.
Genetic and molecular studies have
shown that PCP establishment in Drosophila depends,
in part, on the activation of a signaling pathway
that regulates changes in both cytoskeletal organization
and transcription. It is an atypical Wnt pathway mediated
by Frizzled (Fz), a transmembrane receptor-like molecule
and requires the cytoplasmic Dishevelled (Dsh) protein.
Downstream of these proteins are included Rho GTPases,
a JNK/P38 module and transcription factors like Jun.
Besides the components of the PCP pathway, other polarity
genes have been identified. Some of them are required
in several tissues, but others are though to function
as their effectors, executing specific responses in
particular tissues.
Recently,
it has been demonstrated that many of the genes that
function in PCP in the fly also function during convergent
extension, a morphogenetic movement that occurs during
vertebrate development. Moreover, the process of dorsal
closure in Drosophila embryogenesis has several overlapping
requirements with PCP. Thus, the study of PCP generation
in Drosophila serves as a general model system for
knowing the regulation of related processes in vertebrates,
and for linking signaling pathways to cellular organization
and changes in shape.
In such scenario, our group is interested in the study
of new Drosophila genes involved in PCP establishment,
identified in several genetic screens. We are currently
testing their role in this process, and we want to
determine whether the vertebrate homologs of these
genes function during convergent extension..
