Biology subjects

Kirschner, M. W.

Publications and source records attributed to Kirschner, M. W..

5 recordsLinked to original sources

bioRxiv2018

The jellyfish genome sheds light on the early evolution of active predation

BackgroundUnique among cnidarians, jellyfish have remarkable morphological and biochemical innovations that allow them to actively hunt in the water column. One of the first animals to become free-swimming, jellyfish employ pulsed jet propulsion and venomous tentacles to capture prey.\n\nResultsTo understand these key innovations, we sequenced the genome of the giant Nomuras jellyfish (Nemopilema nomurai), the transcriptomes of its bell and tentacles, and transcriptomes across tissues and developmental stages of the Sanderia malayensis jellyfish. Analyses of Nemopilema and other cnidarian genomes revealed adaptations associated with swimming, marked by codon bias in muscle contraction and expansion of neurotransmitter genes, along with expanded Myosin type II family and venom domains; possibly contributing to jellyfish mobility and active predation. We also identified gene family expansions of Wnt and posterior Hox genes, and discovered the important role of retinoic acid signaling in this ancient lineage of metazoans, which together may be related to the unique jellyfish body plan (medusa formation).\n\nConclusionsTaken together, the jellyfish genome and transcriptomes genetically confirm their unique morphological and physiological traits that have combined to make these animals one of the worlds earliest and most successful multi-cellular predators.

genomics↗

bioRxiv2017

Mouse embryonic stem cells can differentiate via multiple paths to the same state

In embryonic development, cells must differentiate through stereotypical sequences of intermediate states to generate mature states of a particular fate. By contrast, direct programming can generate similar fates through alternative routes, by directly expressing terminal transcription factors. Yet the cell state transitions defining these new routes are unclear. We applied single-cell RNA sequencing to compare two mouse motor neuron differentiation protocols: a standard protocol approximating the embryonic lineage, and a direct programming method. Both undergo similar early neural commitment. Then, rather than transitioning through spinal intermediates like the standard protocol, the direct programming path diverges into a novel transitional state. This state has specific and abnormal gene expression. It opens a loop or worm hole in gene expression that converges separately onto the final motor neuron state of the standard path. Despite their different developmental histories, motor neurons from both protocols structurally, functionally, and transcriptionally resemble motor neurons from embryos.

developmental biology↗

bioRxiv2017

Cell size sensing in animal cells coordinates growth rates and cell cycle progression to maintain cell size uniformity

The uniformity of cell size in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether growth rates of individual cells depend on cell size, by combining time-lapse microscopy and immunofluorescence to monitor how variance in cell size changes as cells grow. This analysis revealed two periods in the cell cycle when cell size variance decreases in a manner incompatible with unregulated growth, suggesting that cells sense their own size and adjust their growth rate to correct aberrations. Monitoring nuclear growth in live cells confirmed that these decreases in variance reflect a process that selectively inhibits the growth of large cells while accelerating growth of small cells. We also detected cell-size-dependent adjustments of G1 length, which further reduce variability. Combining our assays with chemical and genetic perturbations confirmed that cells employ two strategies, adjusting both cell cycle length and growth rate, to maintain the appropriate size.

cell biology↗

bioRxiv2017

Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length

Animal cells within a tissue typically display a striking regularity in their size. To date, the molecular mechanisms that control this uniformity are still unknown. We have previously shown that size uniformity in animal cells is promoted, in part, by size-dependent regulation of G1 length. To identify the molecular mechanisms underlying this process, we performed a large-scale small molecule screen and found that the p38 MAPK pathway is involved in coordinating cell size and cell cycle progression. Small cells display higher p38 activity and spend more time in G1 than larger cells. Inhibition of p38 MAPK leads to loss of the compensatory G1 length extension in small cells, resulting in faster proliferation, smaller cell size and increased size heterogeneity. We propose a model wherein the p38 pathway responds to changes in cell size and regulates G1 exit accordingly, to increase cell size uniformity.\n\nOne-sentence summaryThe p38 MAP kinase pathway coordinates cell growth and cell cycle progression by lengthening G1 in small cells, allowing them more time to grow before their next division.

cell biology↗

bioRxiv2016

Conformational landscape of the p28-bound human proteasome regulatory particle

The proteasome holoenzyme is activated by its regulatory particle (RP) consisting of two subcomplexes, the lid and the base. A key event in base assembly is the formation of a heterohexameric ring of AAA-ATPases, which is guided by at least four RP assembly chaperones in mammals: PAAF1, p28/gankyrin, p27/PSMD9 and S5b. We determined a cryo-EM structure of the human RP in complex with its assembly chaperone p28 at 4.5-[A] resolution. The Rpn1-p28-AAA subcomplex in the p28-bound RP is highly dynamic and was resolved to subnanometer resolution in seven states, which recapitulate the conformational landscape of the complex. Surprisingly, the p28-bound AAA ring does not form a channel in the free RP. Instead, it spontaneously samples multiple open and closed topologies. Our analysis suggests that p28 guides the proteolytic core particle to select certain conformation of the ATPase ring for RP engagement in the last step of the chaperone-mediated proteasome assembly.

biochemistry↗