Many retinal diseases lead to the loss of retinal neurons and cause visual impairment. The adult mammalian retina has little capacity for regeneration. By contrast, teleost fish functionally regenerate their retina following injury, and Müller glia (MG) are the source of regenerated neurons1–6. The proneural transcription factor Ascl1 is upregulated in MG after retinal damage1,7 in zebrafish and is necessary for regeneration8. Although Ascl1 is not expressed in mammalian MG after injury9, forced expression of Ascl1 in mouse MG induces a neurogenic state in vitro10 and in vivo after NMDA (N-methyl-D-aspartate) damage in young mice11. However, by postnatal day 16, mouse MG lose neurogenic capacity, despite Ascl1 overexpression11. Loss of neurogenic capacity in mature MG is accompanied by reduced chromatin accessibility, suggesting that epigenetic factors limit regeneration. Here we show that MG-specific overexpression of Ascl1, together with a histone deacetylase inhibitor, enables adult mice to generate neurons from MG after retinal injury. The MG-derived neurons express markers of inner retinal neurons, synapse with host retinal neurons, and respond to light. Using an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC–seq), we show that the histone deacetylase inhibitor promotes accessibility at key gene loci in the MG, and allows more effective reprogramming. Our results thus provide a new approach for the treatment of blinding retinal diseases.

Animal eyes have evolved to process behaviorally important visual information, but how retinas deal with statistical asymmetries in visual space remains poorly understood. Using hyperspectral imaging in the field, in vivo 2-photon imaging of retinal neurons, and anatomy, here we show that larval zebrafish use a highly anisotropic retina to asymmetrically survey their natural visual world. First, different neurons dominate different parts of the eye and are linked to a systematic shift in inner retinal function: above the animal, there is little color in nature, and retinal circuits are largely achromatic. Conversely, the lower visual field and horizon are color rich and are predominately surveyed by chromatic and color-opponent circuits that are spectrally matched to the dominant chromatic axes in nature. Second, in the horizontal and lower visual field, bipolar cell terminals encoding achromatic and color-opponent visual features are systematically arranged into distinct layers of the inner retina. Third, above the frontal horizon, a high-gain UV system piggybacks onto retinal circuits, likely to support prey capture.

Although the Notch and JAK-STAT signalling pathways fulfill overlapping roles in growth and differentiation regulation, no coordination mechanism has been proposed to explain their relationship. Here we show that STAT3 is activated in the presence of active Notch, as well as the Notch effectors Hes1 and Hes5. Hes proteins associate with JAK2 and STAT3, and facilitate complex formation between JAK2 and STAT3, thus promoting STAT3 phosphorylation and activation. Furthermore, suppression of endogenous Hes1 expression reduces growth factor induction of STAT3 phosphorylation. STAT3 seems to be essential for maintenance of radial glial cells and differentiation of astrocytes by Notch in the developing central nervous system. These results suggest that direct protein-protein interactions coordinate cross-talk between the Notch-Hes and JAK-STAT pathways.

Summary In the eye, the function of same-type photoreceptors must be regionally adjusted to process a highly asymmetrical natural visual world. Here, we show that UV cones in the larval zebrafish area temporalis are specifically tuned for UV-bright prey capture in their upper frontal visual field, which may use the signal from a single cone at a time. For this, UV-photon detection probability is regionally boosted more than 10-fold. Next, in vivo two-photon imaging, transcriptomics, and computational modeling reveal that these cones use an elevated baseline of synaptic calcium to facilitate the encoding of bright objects, which in turn results from expressional tuning of phototransduction genes. Moreover, the light-driven synaptic calcium signal is regionally slowed by interactions with horizontal cells and later accentuated at the level of glutamate release driving retinal networks. These regional differences tally with variations between peripheral and foveal cones in primates and hint at a common mechanistic origin.

The transcription factor STAT3 promotes astrocytic differentiation of neural precursor cells (NPCs) during postnatal development of the mouse neocortex, but little has been known of the possible role of STAT3 in the embryonic neocortex. We now show that STAT3 is expressed in NPCs of the mouse embryonic neocortex and that the JAK-STAT3 signaling pathway plays an essential role in the maintenance of NPCs by fibroblast growth factor 2. Conditional deletion of the STAT3 gene in NPCs reduced their capacity to form neurospheres in vitro, as well as promoted neuronal differentiation both in vitro and in vivo. Furthermore, STAT3 was found to maintain NPCs in the undifferentiated state in a non-cell-autonomous manner. STAT3-dependent expression of the Notch ligand Delta-like1 (DLL1) appears to account for the non-cell-autonomous effect of STAT3 on NPC maintenance, as knockdown of DLL1 by RNA interference or inhibition of Notch activation with a ␥-secretase inhibitor abrogated the enhancement of neurosphere formation by STAT3. Our results reveal a previously unrecognized mechanism of interaction between the JAK-STAT3 and DLL1-Notch signaling pathways, as well as a pivotal role for this interaction in maintenance of NPCs during early neocortical development.

When the formation of Müller glia is inhibited in the zebrafish retina, a major consequence is that the retina begins to rip apart due to a loss of the mechanical resilience that these glial cells provide to the neural tissue.

For colour vision, retinal circuits must separate information about intensity and wavelength. This requires circuit level comparison of at least two spectrally distinct photoreceptors. However, many vertebrates use four or more, and in those cases the nature and implementation of this computation remains poorly understood. Here, we establish the complete circuit architecture and function of outer retinal circuits underlying colour processing in the tetrachromatic larval zebrafish. Our findings reveal that the specific spectral tunings of the four cone types near optimally rotate the encoding of natural daylight in a principal component analysis (PCA)−like manner to yield one primary achromatic axis, two colour opponent axes as well as a secondary UV-achromatic axis for prey capture. We note that fruit flies − the only other tetrachromat species where comparable circuit-level information is available − use essentially the same strategy to extract spectral information from their relatively blue-shifted terrestrial visual world. Together, our results suggest that rotating colour space into achromatic and chromatic axes at the eye′s first synapse may be a fundamental principle of colour vision when using more than two spectrally well separated photoreceptor types.

Summary In vertebrate vision, the tetrachromatic larval zebrafish permits non-invasive monitoring and manipulating of neural activity across the nervous system in vivo during ongoing behavior. However, despite a perhaps unparalleled understanding of links between zebrafish brain circuits and visual behaviors, comparatively little is known about what their eyes send to the brain via retinal ganglion cells (RGCs). Major gaps in knowledge include any information on spectral coding and information on potentially critical variations in RGC properties across the retinal surface corresponding with asymmetries in the statistics of natural visual space and behavioral demands. Here, we use in vivo two-photon imaging during hyperspectral visual stimulation as well as photolabeling of RGCs to provide a functional and anatomical census of RGCs in larval zebrafish. We find that RGCs’ functional and structural properties differ across the eye and include a notable population of UV-responsive On-sustained RGCs that are only found in the acute zone, likely to support visual prey capture of UV-bright zooplankton. Next, approximately half of RGCs display diverse forms of color opponency, including many that are driven by a pervasive and slow blue-Off system—far in excess of what would be required to satisfy traditional models of color vision. In addition, most information on spectral contrast was intermixed with temporal information. Taken together, our results suggest that zebrafish RGCs send a diverse and highly regionalized time-color code to the brain.