Our laboratory is interested in understanding the role of primary cilia during tissue morphogenesis and repair. We are using the anterior segment of the eye as a novel paradigm to address this question. Our approach involves mouse genetics in combination with advance microscopy, genomic technology and biochemistry.
Primary cilia are microtubule-based cellular organelles that assemble at the cellular surface and organize sensory transduction including Shh, calcium and cell polarization signaling. Although several ultrastructural studies documented cilia morphology and presence in many vertebrate tissues and cell types it wasn’t until recent years that their protein composition started to be uncovered. However, much remains to be determined regarding their biogenesis and function during development, homeostasis and regeneration of complex tissues. Disfunctional cilia lead to a class of inherited human diseases collectively called “ciliopathies” and characterized by loss of vision, obesity, mental retardation and morphogenetic defects in many tissues. Ciliopathies such as Meckel, Bardet-Biedel and Joubert syndromes present conditions of the anterior segment of the eye including poorly understood disorders such as abnormal iridocorneal angle, sclerocornea, keratoconus, microphthalmia, microcornea, glaucoma, corneal thickening, edema, and cataract
We have recently shown that primary cilia play an essential role in instructing cellular remodeling and tissue morphogenesis during development and repair of corneal cell layers.
Fig. 1. Cilia assembly, cellular remodeling and basal body polarization of CECS during CE repair. A and B) Wounded area of CE 18h and 30hr after in vivo recovery. Corneas were dissected from 3 month old mice. C) Intact area of the same CE shown in B). D) Basal body distance from the cell median, measured as shown by the dotted line in the bottom panel of B). E) Model of the cilia dynamics during cellular morphogenesis in development and repair (Blitzer, 2011 PNAS).
Our long-term goals are:
1) To elucidate the role of primary cilia in signaling pathways required for proper cell differentiation and tissue patterning during corneal development.
2) To identify new cilia-related therapeutic targets to counteract corneal cell loss, due to aging, trauma or diseases, and improve corneal repair.
Fig. 2. Ablation of IFT88 induces accumulation of CEC in the suprabasal layer and abnormal CE thickening. TEM image of central CE of adult K14Ift88 cKO (left panel) clearly reveals the accumulation of epithelial cells in the immediate suprabasal layer when compared to that of control corneas (right panel). Yellow highlights indicate suprabasal cells confined between basal and superficial cell layers.
3) To uncover the role of primary cilia during eye development with a particular focus on congenital anterior segment diseases and glaucoma.