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Cilia are hair-like protrusions of the cellular membrane that are held in place by an inner skeleton made of microtubules, a special kind of protein fiber. The adjacent figure shows a schematic of a cilium with all its parts. Cilia were already present in the last eukaryotic common ancestor (LECA), a unicellular organism that lived around two billion years ago. In LECA, cilia multitasked as both


propellers and antennae, thereby allowing this ancient creature to both swim and sense its environment. LECA's offspring in today's world includes all unicellular (protists) and multicellular (animals, plants & fungi) eukaryotic organisms. Many of these descendants still have cilia. Nevertheless, while protist cilia still multitask as they did in LECA, cilia in multicellular eukaryotes have specialized to perform cell type-specific functions. Thus, some cell types harbor motile cilia that propel extracellular fluid, while other cell types contain primary cilia that sense optical, mechanical or chemical signals.

Congenital defects in ciliary genes give rise to the ciliopathies, a collection of human diseases that are very diverse regarding their prevalence, severity, genetics and symptoms. Some ciliopathies are fairly common (like autosomal dominant polycystic kidney disease, affecting 1 in 800 people), while others are rare (such as Joubert syndrome, a recessive disorder affecting 1 in 100,000 individuals). Ciliopathies can be caused by mutations in many different ciliary genes, they can be inherited in many different patterns,


and they can cause a wide variety of symptoms, including retinal degeneration, cystic kidneys, obesity and congenital malformations of brain, limbs and skeleton, among others (see juxtaposed figure and table).

Many ciliopathy-associated malformations are due to defects in Hedgehog (Hh) signaling, a ciliary signaling pathway essential for embryonic development and adult stem cell function. Abnormal activation of ciliary Hh signaling may lead to cancer, as is the case in many cases of medulloblastoma (the most common malignant brain tumor in children) and basal cell carcinoma (the most common of all cancers).

Besides their well-established roles in ciliopathies and cancer, it is becoming clear that cilia also play roles in other diseases, including such major diseases as diabetes and Alzheimer's.


In our lab, we study the molecular bases of ciliary signaling, with emphasis on the Hh pathway. More precisely, we are addressing the following questions:

(1) How are ciliary PIP levels regulated?

Phosphoinositides (PIPs) are phosphorylated derivatives of phosphatidylinositol (PI), a membrane lipid (see figure). We have shown that the ciliary membrane is enriched in PI4P and

depleted of PI(4,5)P2, and that this is required for optimal Hh responsiveness. Moreover, we showed that Inpp5e, a ciliopathy-associated ciliary enzyme, is responsible for maintaining ciliary PIP levels. We are now studying how Inpp5e activity is regulated by extracellular signals via phosphorylation.


(2) How do PIPs regulate ciliary membrane composition?

The best known effector of ciliary PIPs is TULP3, a PI(4,5)P2-binding protein that is required for the ciliary localization of several receptors, such as the Hh pathway repressor GPR161 and the Polycystin proteins, whose mutations cause PKD. Recent work shows that TULP3 binds ciliary targeting sequences in these receptors in a  PI(4,5)P2-dependent manner. We are now exploring how these TULP3-receptor interactions are regulated, and what the molecular mechanisms of this regulation are.

(3) How do PIPs regulate ciliary transition zone function?

We are exploring how PIPs associate with certain proteins located at the ciliary transition zone, and how these interactions affect the ciliogenic and ciliary gate functions of the transition zone.


We have already mentioned the massive importance primary cilia have for the correct assembly and operation of our bodies, and some of the diseases caused by their malfunction. Although the main focus of our lab is to perform basic research aimed at increasing our knowledge of these fascinating cellular antennae, our research has had and will continue to have an impact on the lives of real people. Here are some ways in which our research truly matters:

Identification of ciliopathy-causative genes: Our previous research has led to the identification of new ciliopathy genes, thereby helping families better understand the causes of their afflictions, and providing knowledge upon which future therapeutic approaches may be based. In particular, we identified TCTN1 as a causative gene in Joubert syndrome (Garcia-Gonzalo et al. 2011), TMEM231 in Oral-Facial-Digital syndrome type 3 (Roberson et al. 2015), and TMEM17, TMEM138 and TMEM231 in Oral-Facial-Digital syndrome type 6 (Li et al. 2016).


Elucidation of ciliopathy mechanisms: In the past, we have made major contributions to our understanding of how ciliopathy proteins work, and what happens when they stop working. We discovered a ciliopathy protein complex that localizes to the ciliary transition zone, where it acts as a ciliary border patrol controlling what can get in and out of cilia (Garcia-Gonzalo et al. 2011). And we also identified how another ciliopathy protein INPP5E, by regulating ciliary PIP levels, controls ciliary composition and Hh signaling (Garcia-Gonzalo et al. 2015). Again, by providing a more detailed molecular understanding of these diseases, we are laying the groundwork upon which new therapeutic or palliative strategies can be based.

Defining new targets for pharmacological intervention:
In 2012, the US Food and Drug Administration (FDA) approved Vismodegib (Erivedge┬«) for the treatment of basal cell carcinoma. Vismodegib thus became the first and so far only FDA-approved drug to target the Hh pathway, which it does by antagonizing the ciliary protein Smoothened. However, tumors often develop resistance to Vismodegib, emphasizing the need for alternative treatments. Our research will provide detailed molecular data regarding the regulation of other Hh pathway regulators, such as INPP5E and GPR161. By studying


how the function of these proteins is controlled by the likes of phosphorylation, protein-protein interactions, protein-lipid interactions, or conformational changes, we will reveal potential pharmacological targets on these proteins. And the same applies to other ciliary receptors we are studying, which are involved in other ciliary signaling pathways. For example, by identifying the mechanisms controlling the ciliary localization of serotonin receptor-6, our research may help design drugs that alter the receptor's ciliary localization, which may be valuable for the treatment of certain mental disorders.


Facultad de Medicina UAM             C/ Arzobispo Morcillo, 4        
28029 Madrid


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