A cis-regulatory module underlies retinal ganglion cell genesis and axonogenesis
Kamakshi Mehta,
Marwa Daghsni,
Reza Raeisossadati,
Zhongli Xu,
Emily Davis,
Abigail Naidich,
Bingjie Wang,
Shiyue Tao,
Shaohua Pi,
Wei Chen,
Dennis Kostka,
Silvia Liu,
Jeffrey M. Gross,
Takaaki Kuwajima,
Issam Aldiri
Affiliations
Kamakshi Mehta
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Marwa Daghsni
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Reza Raeisossadati
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
Zhongli Xu
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Emily Davis
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Abigail Naidich
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Bingjie Wang
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Shiyue Tao
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Shaohua Pi
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Wei Chen
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Dennis Kostka
Department of Computational & Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Silvia Liu
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Jeffrey M. Gross
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
Takaaki Kuwajima
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Issam Aldiri
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Computational & Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Corresponding author
Summary: Atoh7 is transiently expressed in retinal progenitor cells (RPCs) and is required for retinal ganglion cell (RGC) differentiation. In humans, a deletion in a distal non-coding regulatory region upstream of ATOH7 is associated with optic nerve atrophy and blindness. Here, we functionally interrogate the significance of the Atoh7 regulatory landscape to retinogenesis in mice. Deletion of the Atoh7 enhancer structure leads to RGC deficiency, optic nerve hypoplasia, and retinal blood vascular abnormalities, phenocopying inactivation of Atoh7. Further, loss of the Atoh7 remote enhancer impacts ipsilaterally projecting RGCs and disrupts proper axonal projections to the visual thalamus. Deletion of the Atoh7 remote enhancer is also associated with the dysregulation of axonogenesis genes, including the derepression of the axon repulsive cue Robo3. Our data provide insights into how Atoh7 enhancer elements function to promote RGC development and optic nerve formation and highlight a key role of Atoh7 in the transcriptional control of axon guidance molecules.
