Genetic control of retina development

Recent studies leave no doubt that there are strict genetic mechanisms in place for controlling major aspects of neuronal development. My thesis explores how these mechanisms control two important aspects of retinal neuron development: cell fate specification and polarization. To this end, I pursued two different strategies. Focusing on amacrine cells, a remarkably diverse population of retinal neurons, I explored the developmental strategy for generating cellular diversity in mouse retina. Then, I investigated the role of a known cortical polarization pathway for retina polarity.;First, I asked whether a correlation exists between birthdates and subtype identity. To this end, I defined several subset markers for amacrine cells. In doing so, I identified a novel marker for an atypical population of amacrine cells, potentially not using any of the neurotransmitters heretofore identified in retina. I then went on to use this marker and others to determine the time interval for the genesis of different subtypes of amacrine cells. I showed that there is not only a correlation between birthdate and subtype, but also a correlation between birthdate and soma position. My results show that the mechanisms similar to those involved in determining the main cell fates in retina and cerebral cortex may also be involved in specifying subtype identity.;Second, I tested the hypothesis that three kinases previously shown to be necessary for polarization of cortical neurons, LKB1, SAD-A, and SAD-B also play roles in the polarization of retinal neurons. In cortex, SAD kinases are downstream effectors of LKB1. I analyzed conditional mutant mice and showed that while LKB1 is required for the proper morphology of retinal neurons, SAD kinases are dispensable. This suggests that other substrates are involved in mediating LKB1 function in the retina. Further experiments suggest that LKB1 deficiency alters photoreceptor maturation and metabolism, alteration that further triggers other abnormalities of LKB1 mutant retina.