Ciliary Signaling Mechanisms
Developmental Molecular Biology
Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM (IIBM)
DESCRIPTION OF THE OFFER
Cilia are microtubule-based plasma membrane protrusions emanating from a specialized centriole known as basal body. Conserved from unicellular eukaryotes to humans, cilia perform motor and/or sensory functions. Sensory cilia, often referred to as primary cilia, specialize in the reception and transduction of optical, mechanical and chemical signals (photons, blood and urine flow, odorants, morphogens, hormones, etc.).
Cilia dysfunction causes ciliopathies, diseases that can affect one (as in retinitis pigmentosa or polycystic kidney disease) or multiple organs (as in Meckel, Joubert or Bardet-Biedl syndromes). Many ciliopathy-associated congenital malformations are due to defects in Hedgehog (Hh) signaling, a ciliary signal transduction pathway essential for embryonic development. In adults, Hh signaling controls stem cell function and its ectopic activation leads to cancer.
In our lab, we study the molecular bases of ciliary signaling, with emphasis on the Hh pathway. More precisely, we are addressing these two questions:
(1) Role of phosphoinositides in ciliary signaling. We have shown that the ciliary membrane is enriched in PI(4)P and depleted of PI(4,5)P2, and that this is required for optimal Hh responsiveness. Moreover, we have shown that Inpp5e, a ciliopathy-associated ciliary enzyme, is responsible for maintaining ciliary phosphoinositide composition. We now want to understand how these phosphoinositides regulate Hh signaling, and whether this also applies to other ciliary signaling pathways (Garcia-Gonzalo et al. 2015 Developmental Cell).
(2) Role of the transition zone in ciliary signaling. The transition zone (TZ) is the region at the ciliary base separating the cilium from the rest of the cell. We have described a ciliopathy-associated TZ protein complex whose disruption prevents the correct targeting of a number of ciliary membrane proteins, including Inpp5e, Polycystin-2 (mutated in polycystic kidney disease) and Smoothened (whose ciliary accumulation is a key step in Hh pathway activation). We now want to know how these TZ proteins affect the ciliary localization of these signaling proteins (Garcia-Gonzalo et al. 2011 Nature Genetics).
Biomolecules & Cell D.
Pablo Barbeito González
Francesc Garcia Gonzalo