@article {105897, title = {Cx3Cr1-Cre induction leads to microglial activation and IFN-1 signaling caused by DNA damage in early postnatal brain.}, journal = {Cell Rep}, volume = {38}, year = {2022}, month = {2022 Jan 18}, pages = {110252}, abstract = {

Cx3cr1-driven Cre recombinase (Cre) is a widely used genetic tool for enabling gene manipulation in microglia and macrophages. However, an in-depth analysis of the possible detrimental effects of Cre activity in microglia, surprisingly, remains missing. Here, we demonstrate an age-dependent sensitivity of microglia to Cx3cr1-Cre toxicity, wherein Cre induction, specifically in early postnatal microglia, is detrimental to microglial development, proliferation, and function. Tamoxifen (TAM)-induced Cre activity leads to microglial activation, type 1 interferon (IFN-1) signaling, and increased phagocytosis, causing aberrant synaptic pruning during the early postnatal period and anxious behavior at later age. The detrimental effects of Cre induction are caused by DNA-damage-induced toxicity in microglia and are limited to the early postnatal period, showing no detrimental effects in adult microglia. Thus, our study reveals an age-dependent vulnerability of microglia to Cre activity, thereby highlighting age dependency of Cre action, which could be especially applicable in the broader context of environment-responsive cell types.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2021.110252}, author = {Sahasrabuddhe, Vinaya and Ghosh, HS} } @article {93672, title = {Adult neural stem cells have latent inflammatory potential that is kept suppressed by to facilitate adult neurogenesis.}, journal = {Sci Adv}, volume = {7}, year = {2021}, month = {2021 May}, abstract = {

Inflammation is known to adversely affect adult neurogenesis, wherein the source of inflammation is largely thought to be extraneous to the neurogenic niche. Here, we demonstrate that the adult hippocampal neural progenitors harbor an inflammatory potential that is proactively suppressed by transcription factor 4 (). Deletion of in hippocampal -expressing progenitors causes loss of proliferative capacity and acquisition of myeloid inflammatory properties. This transformation abolishes their differentiation potential and causes production of detrimental factors that adversely affect niche cells, causing inflammation in the dentate gyrus. Thus, on one hand, deletion causes abrogation of proliferative progenitors leading to reduction of adult neurogenesis, while on the other, their accompanying inflammatory transformation inflicts inflammation in the niche. Taken together, we provide the first evidence for a latent inflammatory potential of adult hippocampal neural progenitors and identify as a critical regulator that facilitates adult neurogenesis via proactive suppression of this detrimental potential.

}, issn = {2375-2548}, doi = {10.1126/sciadv.abf5606}, author = {Shariq, Mohammad and Sahasrabuddhe, Vinaya and Krishna, Sreevatsan and Radha, Swathi and Bellampalli, Ravishankara and Dwivedi, Anukriti and Cheramangalam, Rajit and Reizis, Boris and H{\'e}bert, Jean and Ghosh, Hiyaa S} } @article {3547, title = {Large-Effect Beneficial Synonymous Mutations Mediate Rapid and Parallel Adaptation in a Bacterium.}, journal = {Mol Biol Evol}, year = {2016}, month = {2016 Feb 23}, abstract = {

Contrary to previous understanding, recent evidence indicates that synonymous codon changes may sometimes face strong selection. However, it remains difficult to generalize the nature, strength, and mechanism(s) of such selection. Previously, we showed that synonymous variants of a key enzyme-coding gene (fae) of Methylobacterium extorquens AM1 decreased enzyme production and reduced fitness dramatically. We now show that during laboratory evolution, these variants rapidly regained fitness via parallel yet variant-specific, highly beneficial point mutations in the N-terminal region of fae. These mutations (including four synonymous mutations) had weak but consistently positive impacts on transcript levels, enzyme production, or enzyme activity. However, none of the proposed mechanisms (including internal ribosome pause sites or mRNA structure) predicted the fitness impact of evolved or additional, engineered point mutations. This study shows that synonymous mutations can be fixed through strong positive selection, but the mechanism for their benefit varies depending on the local sequence context.

}, issn = {1537-1719}, doi = {10.1093/molbev/msw035}, author = {Agashe, Deepa and Sane, Mrudula and Phalnikar, Kruttika and Diwan, Gaurav D and Habibullah, Alefiyah and Martinez-Gomez, Norma Cecilia and Sahasrabuddhe, Vinaya and Polachek, William and Wang, Jue and Chubiz, Lon M and Marx, Christopher J} }