The Putative Transcription Factor Prdm8 is Required for the Differentiation and Maintenance of Rod and Cone Bipolar Cells in the Mammalian Retina

Highly conserved genes that are abundantly and specifically expressed in the retina are likely to be important for retinal physiology or development. Prdm8 is expressed abundantly in retina and belongs to the PRDM (PR domain containing) protein family, conserved transcription factors important in the regulation of development and cancer. To begin to understand the role of Prdm8 in the retina, I cloned the cDNA and characterized Prdm8 expression in the mouse. Prdm8 encodes a PR domain and three zinc finger domains and is expressed predominantly in the developing and mature nervous system, including the retina, hippocampus and cerebellum. In the developing retina, Prdm8 mRNA is enriched in differentiating neurons. Together, these findings suggested that Prdm8 might be important for both neural development and maintenance. To determine whether Prdm8 is necessary for neural development, I generated Prdm8 null mice. Prdm8eGFP/eGFP mice are born at expected Mendelian ratios and viable, but have a hypocellular retina, develop prominent ventral skin lesions and display defects in hindlimb coordination, impaired spatial learning and memory, and changes in the volume of brain substructures. To better understand the role of Prdm8 in development, I focused on the Prdm8eGFP/eGFP retinal phenotype. I determined that Prdm8 is expressed in subsets of bipolar, amacrine and ganglion cells, and at a low level in photoreceptors. In the Prdm8eGFP/eGFP retina, cell loss was restricted to the inner nuclear layer, due to a lack of rod bipolar and cone bipolar subtypes. I found that bipolar cells were specified, but lost due to a failure in maturation, including a decrease in Vsx1 and Bhlhb4 expression, two transcription factors necessary for bipolar cell development. Consistent with this defect, Prdm8eGFP/eGFP mice exhibited impaired electroretinogram b-wave responses. Given the abundant expression of Prdm8 in the developing and mature nervous system and the array of neurobehavioural phenotypes identified, Prdm8 is likely to be necessary for development in other regions of the brain. My work provides novel insight into the genetic control of visual disorders and a useful framework for understanding the role of Prdm8 and this class of transcription factors in the development of other parts of the nervous system.Ph