Biology subjects

McCullough, M.

Publications and source records attributed to McCullough, M..

3 recordsLinked to original sources

bioRxiv2021

fmr1 mutation interacts with sensory experience to alter the early development of behavior and sensory coding in zebrafish

While Autism Spectrum Disorders (ASDs) are developmental in origin little is known about how they affect the early development of behavior and sensory coding, or how this is modulated by the sensory environment. The most common inherited form of autism is Fragile X syndrome, caused by a mutation in FMR1. Here we show that zebrafish fmr1-/- mutant larvae raised in a naturalistic visual environment display early deficits in hunting behavior, tectal map development, tectal network properties and decoding of spatial stimuli. However when given a choice they preferred an environment with reduced visual stimulation, and rearing them in this environment improved these metrics. Older fmr1-/- fish showed differences in social behavior, spending more time observing a conspecific, but responding more slowly to social cues. Together these results help reveal how fmr1-/- changes the early development of vertebrate brain function, and how manipulating the environment could potentially help reduce these changes.

neuroscience↗

bioRxiv2021

Loss of HMCES is synthetic lethal with APOBEC activity in cancer cells

Analysis of cancer mutagenic signatures provides information about the origin of mutations and can inform the use of clinical therapies, including immunotherapy. In particular, APOBEC3A (A3A) has emerged as a major driver of mutagenesis in cancer cells and its expression results in DNA damage and susceptibility to treatment with inhibitors of the ATR and CHK1 checkpoint kinases. Here we report the implementation of CRISPR/Cas9 genetic screening to identify susceptibilities of multiple A3A-expressing lung adenocarcinoma cell lines. We identify HMCES, a protein recently linked to the protection of abasic sites, as a central protein for the tolerance of A3A expression. HMCES depletion results in synthetic lethality with A3A expression specifically in a TP53-mutant background. Analysis of previous screening data reveals a strong association between A3A mutational signatures and sensitivity to HMCES loss and indicates that HMCES is specialized in protecting against a narrow spectrum of DNA damaging agents in addition to A3A. We experimentally show that both HMCES disruption and A3A expression increase susceptibility of cancer cells to ionizing radiation, oxidative stress and ATR inhibition; strategies that are often applied in tumor therapies. Overall, our results suggest that HMCES is an attractive target for selective treatment of A3A expressing tumors.

cancer biology↗

bioRxiv2019

Behavioral signatures of a developing neural code

During early life neural codes must develop to appropriately transform sensory inputs into behavioral outputs. Here we demonstrate a direct link between the maturity of neural coding in the visual brain and developmental changes in visually-guided behavior. In zebrafish larvae we show that visually-driven hunting behavior improves from 4 to 15 days post-fertilization, becoming faster and more accurate. During the same period population activity in the optic tectum refines, leading to improved decoding and information transmission of spatial position, particularly in the representation of the frontal visual field. Remarkably, individual differences in decoding can predict each fishs hunting success. Together these results show how the neural codes required to subserve a natural behavior emerge during development.

neuroscience↗