The inner ear is one of the most complex three-dimensinal organs of our head, however it is still little understood how cells organize during development to generate this complex organ. We are studying several morphogenetic events to understand the interaction between cell polarity, cell remodeling, migration and cytoskeleton rearrangements with mechanical properties and signalling cues.
Currently we are studying several morphogenetic processes
Formation of lumens
In zebrafish the cavity of the inner ear is originated by cord hollowing. Initially two small lumens are initiated at the anterior and posterior poles of the placode and following an unzipping sequence they fuse into a central and larger lumen. The expansion mechanism involves an anisotropic epithelial thinnnig of the otic cells and mechanical forces during mitotic rounding that pull the luminal membrane.
We are currently studying what determines the number and position of initial lumens foci established at the placode. Are there any cellular or mechanical constrains that determines this? Which drives epithelial organization to generate a lumen foci?
Sensory neuron delamination and migration
Neural specification begins within the otic placode by the activation of neurog1 in otic stem cells in the most anterior-lateral domain (Abello et al, 2007). The epithelial neurogenic progenitors divide, activate a set of differentiation factors and reorganize prior to their exit from the epithelium. After their delamination, neuroblasts transit-amplify, migrate coordinately and coalesce into the statoacoustic ganglion. How the neuroblasts delaminate out of the otic primordium has little been studied.
Currently we are investigating the cellular and molecular cues regulating the transition from an epithelial neural progenitor to a "mesenchymal-neuronal" phenotype.
After their delamination, how neuroblasts move through the SAG? Do they communicate to each other to follow a specific path?
Columnar Epithelial morphogenesis
Cranial placodes derive from the preplacodal region (PPR), a common domain in which placodal precursors are interspead. During development, these precursors segregate and coalesce into individual placodes. In zebrafish, the PPR cells display a weak epithelial morphology but during the formation of placodes these cells elongate, acquire apico-basal polarity, tight juntions and initiate interkinetic nuclear migration (IKNM). The sequence of events taking place, their relation is not understood, or the transcription factors in the top of the hierarchy driving placodal epithelialization. The lab is studying these questions in the zebrafish otic placode.
2- Neurovascular development
Most attention to understand SAG growth has focused into signals from the ganglion itself. we have created an anatomical map of the network of blood veseels covering the SAG (LT and BA, unpublished results). Blood vessels and nerve fibers course through the body in complicated patters, often aligned one to the other. In recent years, it has been put in evidence that signaling interaction "vessels to nerves" and "nerves to vessels" enables their growth, survival, differentiation and migration in the subventricular zone and other organs.
We are using an avascular mutant (cloche) to study the role of blood vessels in otic neural development
3- Molecular Mechanisms of Hair Cell regeneration
While mammalian vertebrates cannot regenerate damaged hair cells, this ability has been retained in non-mammalian vertebrates. We are studying in zebrafish the molecular mechanisms favoring hair cell renewal in the crista and neuromasts and demostrated that retinoic acid pathway is required for the repression of sox2 and p27kip in supporting cells and initiation of cell proliferation after hair cell damage. Under current work is the study of how retinoic acid interacts with other well established pathways and the epigenomic modifications under regeneration conditions.