2013 Theses Doctoral
The Albino Mouse Visual System: How Perturbed Retinal Development Leads to Altered Binocular Projections
Albinism is a heterogeneous disorder that occurs when one of several genetic defects causes a disruption in melanin synthesis in the hair, skin, and eyes. Every form of albinism results in hypopigmentation in the retinal pigment epithelium (RPE), the monolayer of epithelial cells surrounding the neural retina. All albino mammals that have been studied display a variety of optic abnormalities, one of which is a reduction in the ipsilateral retinal ganglion cell (RGC) axon projection.
This thesis addresses the question of how the disruption of melanin synthesis in the RPE leads to abnormal chiasmatic decussation by using a mouse model that has a mutation in the gene encoding tyrosinase, an enzyme required for melanin synthesis. Previously, our lab has shown that Zic2, a zinc finger transcription factor that is expressed in ventrotemporal RGCs from E14.5-E17.5, directs the ipsilateral projection. Zic2 regulates several programs of gene expression important for axon guidance and synaptic connectivity. Zic2 is expressed in fewer RGCs in the albino retina, coincident with the decrease in the ipsilateral RGCs and indicating that cell subtype specification is altered in the VT retina of albino mice.
This thesis further characterizes perturbations in RGC genesis and specification in the albino mouse. Analysis of retinogeniculate targeting in the albino mouse revealed a population of contralateral VT RGCS that forms an abnormal patch of terminals in the dorsal lateral geniculate nucleus (dLGN) of the mouse, suggestive of misspecification of RGCs in this region. Further, as revealed by expression of Islet1/2 as a marker of differentiated RGCs, the number of differentiated RGCs in the VT retina is lower in the albino compared to pigmented retina, parallel to the reduction of Zic2+ cells. The decrease in Zic2+ and Islet1/2+ cells was explained by birthdating studies, which demonstrated a delay in the wave of RGC production in the albino VT retina at the time when the ipsilateral projection is established. Thus, this thesis provides a link between neurogenesis and specification in the albino retina.
To further elucidate the role of melanin synthesis in VT RGC specification, I tested the effects of L-Dopa treatment of embryonic mice on retinal development and found that L-Dopa ameliorated the defects associated with the reduced ipsilateral projection in the albino mouse by regulating cell proliferation and production. The studies in this thesis contribute to an understanding of the mechanism that underlies the disruption of binocular pathways in the albino visual system, and should illuminate how the pigment pathway in the RPE contributes to development of the neural retina in wild type mice.
- Bhansali_columbia_0054D_11104.pdf application/pdf 27.4 MB Download File
More About This Work
- Academic Units
- Cellular, Molecular and Biomedical Studies
- Thesis Advisors
- Mason, Carol
- Ph.D., Columbia University
- Published Here
- January 23, 2013