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Functional Genetics Laboratory

​​​Director, Marisa L. Zallocchi, Ph.D.

The main interest of the Functional Genetics Laboratory is to understand the proper development and function of neurosensory cells in the inner ear, eye and olfactory organ, and how they are affected in Usher patients. Usher syndrome is a genetically heterogeneous disorder caused by mutations in 11 different genes encoding a large number of proteins and protein variants. Patients with Usher syndrome are congenitally deaf and have delayed onset and progressive retinitis pigmentosa. A fraction of these patients also have a reduction in the olfactory function.

Our research has shown that Usher proteins form functional complexes at the apical and basal aspect of hair cells (inner ear) and photoreceptors (retina) where they regulate the formation and function of specialized structures. At the apical aspect, hair cells have a true cilium (kinocilium) and microvilli (stereocilia) arrange in a staircase shape, the hair cell bundle. Both the kinocilium and the hair cell bundle are critical for proper function of the mechanotransduction channels that drive the depolarization of the hair cells in response to noise. On the other hand, photoreceptors in the retina have also a true cilium (outer segment) that contains all the necessary molecules involved in the response to light (phototransduction). At the basal aspect, both hair cells and photoreceptors have continuously active synapses, the ribbon synapses, which promote rapid neurotransmitter release and sustained signal transmission.

By using different in vivo and in vitro approaches and different animal models (zebrafish and mice) we were able to demonstrate the existence of Usher complexes involved in protein trafficking. These complexes differentially trafficked to the apical and basal aspect of hair cells where they regulated the formation and maturation of the corresponding specialized structures (hair cell bundle and ribbon synapses, respectively). Recently, we found that the membrane receptor integrin alpha 8, associates with specific Usher protein variants and regulates the formation of the true cilia in the three sensory organs (ear, eye and olfaction). Deciphering the signaling cascade involved in this process is the next step in understanding Usher-integrin complex function in cilia formation.

​Legends to figures:

Figure 1.
Depth code image of the lateral crista of a 3 days post-fertilization zebrafish.

Figure 2.
Filter gradient image of a 5 days post-fertilization neuromast i​mmunostained for the pre-synaptic marker Ribeye b (red) and the post-synaptic marker Maguk (green).