Biology subjects

Mishra, P.

Publications and source records attributed to Mishra, P..

4 recordsLinked to original sources

bioRxiv2018

PUMILIO hyperactivity drives premature aging of Norad-deficient mice

Although numerous long noncoding RNAs (lncRNAs) have been identified, our understanding of their roles in mammalian physiology remains limited. Here we investigated the physiologic function of the conserved lncRNA Norad in vivo. Deletion of Norad in mice results in genomic instability and mitochondrial dysfunction, leading to a dramatic multi-system degenerative phenotype resembling premature aging. Loss of tissue homeostasis in Norad-deficient animals is attributable to augmented activity of PUMILIO proteins, which act as post-transcriptional repressors of target mRNAs to which they bind. Norad is the preferred RNA target of PUMILIO2 (PUM2) in mouse tissues and, upon loss of Norad, PUM2 hyperactively represses key genes required for mitosis and mitochondrial function. Remarkably, enforced Pum2 expression fully phenocopies Norad deletion, resulting in rapid-onset aging-associated phenotypes. These findings provide new insights and open new lines of investigation into the roles of noncoding RNAs and RNA binding proteins in normal physiology and aging.

molecular biology↗

bioRxiv2018

A strain of an emerging Indian pathotype of Xanthomonas oryzae pv. oryzae defeats the rice bacterial blight resistance gene xa13 without inducing a clade III SWEET gene and is nearly identical to a recent Thai isolate

The rice bacterial blight pathogen Xanthomonas oryzae pv. oryzae (Xoo) injects transcription activator-like effectors (TALEs) that bind and activate host susceptibility (S) genes important for disease. Clade III SWEET genes are major S genes for bacterial blight. The resistance genes xa5, which reduces TALE activity generally, and xa13, a SWEET11 allele not recognized by the cognate TALE, have been effectively deployed. However, strains that defeat both resistance genes individually were recently reported in India and Thailand. To gain insight into the mechanism(s), we completely sequenced the genome of one such strain from each country and examined the encoded TALEs. Strikingly, the two strains are clones, sharing nearly identical TALE repertoires, including a TALE known to activate SWEET11 strongly enough to be effective even when diminished by xa5. We next investigated SWEET gene induction by the Indian strain. The Indian strain induced no clade III SWEET in plants harbouring xa13, indicating a pathogen adaptation that relieves dependence on these genes for susceptibility. The findings open a door to mechanistic understanding of the role SWEET genes play in susceptibility and illustrate the importance of complete genome sequence-based monitoring of Xoo populations in developing varieties with effective disease resistance.

pathology↗

bioRxiv2017

Pervasive contingency and entrenchment in a billion years of Hsp90 evolution

Although many potential mutations within proteins modulate each others effects1-4, the extent to which these epistatic interactions influenced the fitness effects of the sequence changes that actually occurred during historical evolution - and thus made molecular evolution contingent and irreversible - is controversial5-16. We addressed this question directly by precisely measuring the fitness effects in both extant and reconstructed ancestral sequence contexts of all historical amino acid substitutions that occurred during the billion-year evolutionary history of the heat shock protein 90 (Hsp90) ATPase domain beginning from a deep eukaryotic ancestor to modern Saccharomyces cerevisiae. We find a pervasive influence of epistasis on historical sequence evolution: the majority of the 98 derived states that evolved during history were deleterious at times before they happened, and the vast majority also became subsequently entrenched6, with the ancestral state becoming deleterious after its substitution. A few of these epistatic interactions were of massive fitness consequence, but the majority were of small but evolutionarily relevant effect size. We find that both the large- and small-effect epistasis were largely caused by specific interactions among sites rather than a general permissive or restrictive effect17. Our results highlight how epistasis continually opens and closes windows of mutational opportunity over evolutionary timescales, producing histories and biological states that reflect, in significant part, the transient internal constraints imposed by a proteins fleeting sequence states.

evolutionary biology↗

bioRxiv2017

Heterogeneities in afferent connectivity dominate local heterogeneities in the emergence of response decorrelation in the dentate gyrus

The ability of a neuronal population to effectuate response decorrelation has been identified as an essential prelude to efficient neural encoding. To what extent are diverse forms of local and afferent heterogeneities essential in accomplishing such response decorrelation in the dentate gyrus (DG)? Here, we incrementally incorporated four distinct forms of biological heterogeneities into conductance-based network models of the DG and systematically delineate their relative contributions to response decorrelation. We incorporated intrinsic heterogeneities by stochastically generating several electrophysiologically-validated basket and granule cell models that exhibited significant parametric variability, and introduced synaptic heterogeneities through randomized local synaptic strengths. In including adult neurogenesis, we subjected the valid model populations to randomized structural plasticity and matched neuronal excitability to electrophysiological data. We assessed networks comprising different combinations of these three local heterogeneities with identical or heterogeneous afferent inputs from the entorhinal cortex. We found that the three forms of local heterogeneities were independently and synergistically capable of mediating significant response decorrelation when the network was driven by identical afferent inputs. Strikingly, however, when we incorporated afferent heterogeneities into the network to account for the unique divergence in DG afferent connectivity, the impact of all three forms of local heterogeneities were significantly suppressed by the dominant role of afferent heterogeneities in mediating response decorrelation. Our results unveil a unique convergence of cellular- and network-scale degeneracy in the emergence of response decorrelation in the DG, and constitute a significant departure from the literature that assigns a critical role for local network heterogeneities in input discriminability.\n\nSIGNIFICANCE STATEMENTThe olfactory bulb and the dentate gyrus (DG) networks assimilate new neurons in adult rodents, with adult neurogenesis postulated to subserve efficacious information transfer by reducing correlations in neuronal responses to afferent inputs. Heterogeneities emerging from the lateral dendro-dendritic synapses, mediated by locally-projecting neurogenic inhibitory granule cells, are known to play critical roles in channel decorrelation in the olfactory bulb. However, the contributions of different heterogeneities in mediating response decorrelation in DG, comprising neurogenic excitatory granule cells projecting beyond DG and endowed with uniquely divergent afferent inputs, have not been delineated. Here, we quantitatively demonstrate the dominance of afferent heterogeneities, over multiple local heterogeneities, in the emergence of response decorrelation in DG, together unveiling cross-region degeneracy in accomplishing response decorrelation.

neuroscience↗