Our accurate vision depends on the flow of visual information through precisely wired connections between axons and dendrites of different retinal neurons. In the retina, neurons occupy spatial domains and arborize their dendrites, which require the proper distribution of their cell bodies and dendritic arbors. Cell bodies of the same type of neurons are spaced out in a process called mosaic patterning, and their dendrites establish a zone within which other cells of the same type are excluded, a process called tiling. In addition, the neurites from an individual cell display self-avoidance properties. In contrast to the excellent progress made in discovering genes and mechanisms of retinal cell fate determination and differentiation, relatively little is known about the molecular mechanisms underlying the mosaic patterning and tiling processes in the retina as well as in other nervous systems. Not until recently, studies show that in mice mutant for Down syndrome cell adhesion molecule (DSCAM), DSCAM-LIKE1 (DSCAML1), MEG10, and PCDH, certain types of retinal amacrine and ganglion cells exhibit defects in the spacing of cell bodies and in the dendritic arborization, which begins to implicate the roles of unique classes of cell adhesion molecules (CAMs) in regulating these processes in the vertebrate retina. Nevertheless, we have yet to uncover the other molecules involved in these processes in each of the nearly 80 retinal cell types and subtypes, and more importantly, to identify and characterize the entire genes and genetic pathways that govern the formation of functional neural circuitry. In the past, this question has been hard to address due to the lack of a suitable molecule. Here, we show that in mice lacking BARHL2, a BAR-homeodomain transcription factor, starburst amacrine cells in the ganglion cell layer have aggregated dendrites and clumped cell bodies, indicating Barhl2's role in self-avoidance. Being the first transcription factor implicated in neuronal mosaic patterning and tiling processes, BARHL2 offers a unique opportunity to ultimately identify genetic pathways of neuronal mosaic patterning and tiling formation. In this proposal, we will fully characterize the mosaic patterning and tiling phenotypes of starburst amacrine cells in the ganglion cell layer of the Barhl2-null retina. Second, to recover the genetic pathway of self-avoidance, we will perform RNA-Seq of Barhl2 wild type and null starburst amacrine cells and BARHL2 ChIP-Seq to screen for downstream target genes of Barhl2 and to identify the transcriptional network regulating the tiling and mosaic patterning processes of starburst amacrine cells. Together, these studies will define the role of Barhl2 in regulating the tiling and mosaic patterning processes of starburst amacrine cells and elucidate the transcriptional events that occur downstream of Barhl2.
Our accurate vision initializes from neurons in the retina and depends on the precisely organized retinal neurons and their interactions. Failure in the development of retinal neurons and their connections leads to impaired vision or blindness. Understanding how retinal neurons and their interactions are formed during development will help us identify the causes of impaired vision and blindness, and develop novel treatments and cures.
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