Simultaneous Requirements for Hes1 in Retinal Neurogenesis and Optic Cup-Stalk Boundary Maintenance.

Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE

Publication: Washington, DC : Society for Neuroscience
Original Publication: [Baltimore, Md.] : The Society, c1981-

Eye/*embryology ; Neurogenesis/*physiology ; Transcription Factor HES-1/*physiology; Animals ; Coloboma/genetics ; Coloboma/pathology ; Ependymoglial Cells/cytology ; Eye/growth & development ; Gastrulation ; Genetic Association Studies ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Microphthalmos/genetics ; Microphthalmos/pathology ; Optic Disk/embryology ; Optic Disk/pathology ; Receptors, Notch/physiology ; Retina/abnormalities ; Retina/embryology ; Retinal Bipolar Cells/cytology ; Retinal Cone Photoreceptor Cells/metabolism ; Retinal Ganglion Cells/cytology ; Signal Transduction ; Transcription Factor HES-1/deficiency ; Transcription Factor HES-1/genetics

The bHLH transcription factor Hes1 is a key downstream effector for the Notch signaling pathway. During embryogenesis neural progenitors express low levels of Hes1 in an oscillating pattern, whereas glial brain boundary regions (e.g., isthmus) have high, sustained Hes1 levels that suppress neuronal fates. Here, we show that in the embryonic mouse retina, the optic nerve head and stalk express high Hes1, with the ONH constituting a boundary between the neural retina and glial cells that ultimately line the optic stalk. Using two Cre drivers with distinct spatiotemporal expression we conditionally inactivated Hes1 , to delineate the requirements for this transcriptional repressor during retinal neurogenesis versus patterning of the optic cup and stalk. Throughout retinal neurogenesis, Hes1 maintains proliferation and blocks retinal ganglion cell formation, but surprisingly we found it also promotes cone photoreceptor genesis. In the postnatal eye, Hes1 inactivation with Rax-Cre resulted in increased bipolar neurons and a mispositioning of Müller glia. Our results indicate that Notch pathway regulation of cone genesis is more complex than previously assumed, and reveal a novel role for Hes1 in maintaining the optic cup-stalk boundary. SIGNIFICANCE STATEMENT The bHLH repressor Hes1 regulates the timing of neurogenesis, rate of progenitor cell division, gliogenesis, and maintains tissue compartment boundaries. This study expands current eye development models by showing Notch-independent roles for Hes1 in the developing optic nerve head (ONH). Defects in ONH formation result in optic nerve coloboma; our work now inserts Hes1 into the genetic hierarchy regulating optic fissure closure. Given that Hes1 acts analogously in the ONH as the brain isthmus, it prompts future investigation of the ONH as a signaling factor center, or local organizer. Embryonic development of the ONH region has been poorly studied, which is surprising given it is where the pan-ocular disease glaucoma is widely believed to inflict damage on RGC axons.
(Copyright © 2020 the authors.)

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P30 EY012576 United States EY NEI NIH HHS; R01 EY013612 United States EY NEI NIH HHS

Keywords: Hes1; Notch signaling; bHLH; gliogenesis; neurogenesis; retina

0 (Hes1 protein, mouse)
0 (Receptors, Notch)
0 (Transcription Factor HES-1)

Date Created: 20200118 Date Completed: 20200819 Latest Revision: 20200819

20240829

PMC7044741

10.1523/JNEUROSCI.2327-19.2020

31949107