Investigation of the mechanisms of vertebrate eye development through analysis of mouse ciliogenesis mutants
Burnett, Jacob Bradley
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Development of the vertebrate eye is a multi-step process that requires the integration of morphogen signals, inductive tissue interactions, and intrinsic cell programs. The eye initially contains uncommitted progenitors with the capacity to develop into optic stalk, retinal pigment epithelium, or neural retina, but how these cells commit to a particular fate is not fully understood. Hedgehog (HH) signaling plays a role in this process, in part by contributing to the establishment of the proximo-distal and dorso-ventral axes within the eye. However, it is not clear how establishment of these axes ultimately leads to specification of distinct optic cell fates. This dissertation provides insight into the mechanisms of HH-mediated optic cell fate specification through the functional characterization of several mouse ciliogenesis regulators: IFT122, IFT172, and CCRK. Ift122, Ift172, and Ccrk mouse mutants all exhibited defects in ciliogenesis as well as in optic patterning and morphogenesis. These phenotypes were associated with abnormal HH signaling. Through extensive genetic epistasis experiments with core components of the HH pathway, these HH signaling defects were shown to functionally contribute to the eye phenotypes of these mutants. Interestingly, the levels of HH pathway activation in these mutants correlated with distinct shifts in optic cell fates, some of which are predicted from the literature and others which are novel. Taken together, this work suggests that optic progenitors sense subtle changes in the levels of HH pathway activity and alter their fate accordingly.