The retinal ganglion cell (RGC) competence factor ATOH7 is dynamically expressed during retinal histogenesis. ATOH7 transcription is controlled by a promoter-adjacent primary enhancer and a remote shadow enhancer (SE). Deletion of the ATOH7 human SE causes nonsyndromic congenital retinal nonattachment (NCRNA) disease, characterized by optic nerve aplasia and total blindness. We used genome editing to model NCRNA in mice. Deletion of the murine SE reduces Atoh7 messenger RNA (mRNA) fivefold but does not recapitulate optic nerve loss; however, SEdel/knockout (KO) trans heterozygotes have thin optic nerves. By analyzing Atoh7 mRNA and protein levels, RGC development and survival, and chromatin landscape effects, we show that the SE ensures robust Atoh7 transcriptional output. Combining SE deletion and KO and wild-type alleles in a genotypic series, we determined the amount of Atoh7 needed to produce a normal complement of adult RGCs, and the secondary consequences of graded reductions in Atoh7 dosage. Together, these data reveal the workings of an evolutionary fail-safe, a duplicate enhancer mechanism that is hard-wired in the machinery of vertebrate retinal ganglion cell genesis.
Maximum likelihood difference scaling was used to measure suprathreshold contrast response difference scales for low-frequency Gabor patterns, modulated along luminance and L-M color directions in normal, protanomalous, and deuteranomalous observers. Based on a signal-detection model, perceptual scale values, parameterized as d , were estimated by maximum likelihood. The difference scales were well fit by a Michaelis-Menten model, permitting estimates of response and contrast gain parameters for each subject. Anomalous observers showed no significant differences in response or contrast gain from normal observers for luminance contrast. For chromatic modulation, however, anomalous observers displayed higher contrast and lower response gain compared to normal observers. These effects cannot be explained by simple pigment shift models, and they support a compensation mechanism to optimize the mapping of the input contrast range to the neural response range. A linear relation between response and contrast gain suggests a neural trade-off between them.
Difficulties
in developing active-site-directed protein tyrosine
phosphatase (PTP) inhibitors have led to the perception that PTPs
are “undruggable”, highlighting the need for new means
to target pharmaceutically important PTPs allosterically. Recently,
we characterized an allosteric-inhibition site on the PTP domain of
Src-homology-2-domain-containing PTP 2 (SHP2), a key anticancer drug
target. The central feature of SHP2’s allosteric site is a
nonconserved cysteine residue (C333) that can potentially be labeled
with electrophilic compounds for selective SHP2 inhibition. Here,
we describe the first directed discovery effort for C333-targeted
allosteric SHP2 inhibitors. By screening a previously reported library
of reversible, covalent inhibitors, we identified a lead compound,
which was modified to yield an irreversible inhibitor (12), that inhibits SHP2 allosterically and selectively through interaction
with C333. These findings provide a novel paradigm for allosteric-inhibitor
discovery on SHP2, one that may help to circumvent the challenges
inherent in targeting SHP2’s active site.
Highlights d Long-term use of color notch filters increases chromatic response in color anomals d No such effects are observed in normal trichromats or a placebo condition d Spontaneous comments of observers suggest that the effects may endure
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