Our neuroscience lab is located on the 5th floor of the Bio2 building just next to the Pacific ocean. We work on neural plasticity including the molecular basis of plasticity, the evolution of synapses, and disease-related impairments of plasticity such as occurs in Alzheimer's disease. Feel free to visit us or send in your comments.

Neveu P, Kye MJ, Qi S, Buchholz DE, Clegg DO, Sahin M, Park IH, Kim KS, Daley GQ, Kornblum HI, Shraiman BI, Kosik KS. MicroRNA Profiling Reveals Two Distinct p53-Related Human Pluripotent Stem Cell States. Cell Stem Cell. 2010 Dec 3;7(6):671-81.

Reprogramming methodologies have provided multiple routes for achieving pluripotency. However, pluripotency is generally considered to be an almost singular state, with subtle differences described between induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs). We profiled miRNA expression levels across 49 human cell lines, including ESCs, iPSCs, differentiated cells, and cancer cell lines. We found that the resulting miRNA profiles divided the iPSCs and hESCs examined into two distinct categories irrespective of the cell line origin. The miRNAs that defined these two pluripotency categories also distinguished cancer cells from differentiated cells. Transcriptome analysis suggested that several gene sets related to p53 distinguished these categories, and overexpression of the p53-targeting miRNAs miR-92 and miR-141 in iPSCs was sufficient to change their classification status. Thus, our results suggest a subdivision of pluripotent stem cell states that is independent of their origin but related to p53 network status.

(c) 2010

Yuraszeck TM, Neveu P, Rodriguez-Fernandez M, Robinson A, Kosik KS, Doyle FJ 3rd. Vulnerabilities in the tau network and the role of ultrasensitive points in tau pathophysiology. PLoS Comput Biol. 2010 Nov 11;6(11):e1000997.

The multifactorial nature of disease motivates the use of systems-level analyses to understand their pathology. We used a systems biology approach to study tau aggregation, one of the hallmark features of Alzheimer's disease. A mathematical model was constructed to capture the current state of knowledge concerning tau's behavior and interactions in cells. The model was implemented in silico in the form of ordinary differential equations. The identifiability of the model was assessed and parameters were estimated to generate two cellular states: a population of solutions that corresponds to normal tau homeostasis and a population of solutions that displays aggregation-prone behavior. The model of normal tau homeostasis was robust to perturbations, and disturbances in multiple processes were required to achieve an aggregation-prone state. The aggregation-prone state was ultrasensitive to perturbations in diverse subsets of networks. Tau aggregation requires that multiple cellular parameters are set coordinately to a set of values that drive pathological assembly of tau. This model provides a foundation on which to build and increase our understanding of the series of events that lead to tau aggregation and may ultimately be used to identify critical intervention points that can direct the cell away from tau aggregation to aid in the treatment of tau-mediated (or related) aggregation diseases including Alzheimer's.

(c) 2010

Shi Y, Zhao X, Hsieh J, Wichterle H, Impey S, Banerjee S, Neveu P, Kosik KS. MicroRNA regulation of neural stem cells and neurogenesis. J Neurosci. 2010 Nov 10;30(45):14931-6. Review.

MicroRNAs are a class of small RNA regulators that are involved in numerous cellular processes, including development, proliferation, differentiation, and plasticity. The emerging concept is that microRNAs play a central role in controlling the balance between stem cell self-renewal and fate determination by regulating the expression of stem cell regulators. This review will highlight recent advances in the regulation of neural stem cell self-renewal and neurogenesis by microRNAs. It will cover microRNA functions during the entire process of neurogenesis, from neural stem cell self-renewal and fate determination to neuronal maturation, synaptic formation, and plasticity. The interplay between microRNAs and both cell-intrinsic and -extrinsic stem cell players, including transcription factors, epigenetic regulators, and extrinsic signaling molecules will be discussed. This is a summary of the topics covered in the mini-symposium on microRNA regulation of neural stem cells and neurogenesis in SFN 2010 and is not meant to be a comprehensive review of the subject.

(c) 2010

Piedrahita D, Hernández I, López-Tobón A, Fedorov D, Obara B, Manjunath BS, Boudreau RL, Davidson B, Laferla F, Gallego-Gómez JC, Kosik KS, Cardona-Gómez GP. Silencing of CDK5 reduces neurofibrillary tangles in transgenic alzheimer's mice. J Neurosci. 2010 Oct 20;30(42):13966-76.

Alzheimer's disease is a major cause of dementia for which treatments remain unsatisfactory. Cyclin-dependent kinase 5 (CDK5) is a relevant kinase that has been hypothesized to contribute to the tau pathology. Several classes of chemical inhibitors for CDK5 have been developed, but they generally lack the specificity to distinguish among various ATP-dependent kinases. Therefore, the efficacy of these compounds when tested in animal models cannot definitively be attributed to an effect on CDK5. However, RNA interference (RNAi) targeting of CDK5 is specific and can be used to validate CDK5 as a possible treatment target. We delivered a CDK5 RNAi by lentiviral or adenoassociated viral vectors and analyzed the results in vitro and in vivo. Silencing of CDK5 reduces the phosphorylation of tau in primary neuronal cultures and in the brain of wild-type C57BL/6 mice. Furthermore, the knockdown of CDK5 strongly decreased the number of neurofibrillary tangles in the hippocampi of triple-transgenic mice (3×Tg-AD mice). Our data suggest that this downregulation may be attributable to the reduction of the CDK5 availability in the tissue, without affecting the CDK5 kinase activity. In summary, our findings validate CDK5 as a reasonable therapeutic target for ameliorating tau pathology.

(c) 2010

Kosik KS. MicroRNAs and cellular phenotypy. Cell. 2010 Oct 1;143(1):21-6. Review.

This Essay explores the notion that specialized cells have unique vulnerabilities to environmental contingencies that microRNAs help to counteract. Given the ease with which new microRNAs evolve, they may serve as ideal facilitators for the emergence of new cell types.

(c) 2010

Srivastava M, Simakov O, Chapman J, Fahey B, Gauthier ME, Mitros T, Richards GS, Conaco C, Dacre M, Hellsten U, Larroux C, Putnam NH, Stanke M, Adamska M, Darling A, Degnan SM, Oakley TH, Plachetzki DC, Zhai Y, Adamski M, Calcino A, Cummins SF, Goodstein DM, Harris C, Jackson DJ, Leys SP, Shu S, Woodcroft BJ, Vervoort M, Kosik KS, Manning G, Degnan BM, Rokhsar DS. The Amphimedon queenslandica genome and the evolution of animal complexity. Nature. 2010 Aug 5;466(7307):720-6.

Sponges are an ancient group of animals that diverged from other metazoans over 600 million years ago. Here we present the draft genome sequence of Amphimedon queenslandica, a demosponge from the Great Barrier Reef, and show that it is remarkably similar to other animal genomes in content, structure and organization. Comparative analysis enabled by the sequencing of the sponge genome reveals genomic events linked to the origin and early evolution of animals, including the appearance, expansion and diversification of pan-metazoan transcription factor, signalling pathway and structural genes. This diverse 'toolkit' of genes correlates with critical aspects of all metazoan body plans, and comprises cell cycle control and growth, development, somatic- and germ-cell specification, cell adhesion, innate immunity and allorecognition. Notably, many of the genes associated with the emergence of animals are also implicated in cancer, which arises from defects in basic processes associated with metazoan multicellularity.

(c) 2010

Banerjee S, Neveu P, Kosik KS. A Coordinated Local Translational Control Point at the Synapse Involving Relief from Silencing and MOV10 Degradation. Neuron, 2009 Dec 24;64(6):871-884.

Persistent changes in synaptic strength are locally regulated by both protein degradation and synthesis; however, the coordination of these opposing limbs is poorly understood. Here, we found that the RISC protein MOV10 was present at synapses and was rapidly degraded by the proteasome in an NMDA-receptor-mediated activity-dependent manner. We designed a translational trap to capture those mRNAs whose spatiotemporal translation is regulated by MOV10. When MOV10 was suppressed, a set of mRNAs--including alpha-CaMKII, Limk1, and the depalmitoylating enzyme lysophospholipase1 (Lypla1)--selectively entered the polysome compartment. We also observed that Lypla1 mRNA is associated with the brain-enriched microRNA miR-138. Using a photoconvertible translation reporter, Kaede, we analyzed the activity-dependent protein synthesis driven by Lypla1 and alpha-CaMKII 3'UTRs. We established this protein synthesis to be MOV10 and proteasome dependent. These results suggest a unifying picture of a local translational regulatory mechanism during synaptic plasticity.

(c) 2009

Sakarya O, Conaco C, Egecioglu O, Solla SA, Oakley TH, Kosik KS. Evolutionary Expansion and Specialization of the PDZ Domains. Mol Biol Evol. 2009 Dec 21

PDZ domains are protein-protein interaction modules widely used to assemble membranous signaling complexes including those found in the neuronal synapse. PDZ-containing genes encoded in metazoan genomes vastly outnumber those in prokaryotes, plants, and fungi. By comparing 40 proteomes to track the evolutionary history of the PDZ domain, we observed that the variety of associations between PDZ and other domains expands greatly along the stem leading to metazoans and choanoflagellates. We asked whether the expansion of PDZ domains was due to random or specific sequence changes. Studying the sequence signatures of 58 PDZ lineages that are common to bilaterian animals, we showed that six common amino acid residues are able to classify 96% of PDZ domains to their correct evolutionary lineage. In PDZ domain-ligand cocrystals, four of these "classifying positions" lie in direct contact with the -1 and -3 residues of the ligand. This suggests coevolution of the more flexible regions of the binding interaction as a central mechanism of specialization inherent within the PDZ domain. To identify these positions, we devised two independent algorithms--a metric termed within-clade entropy (WCE) and an average mutual information (AvgMI) score--that both reached similar results. Extending these tools to the choanoflagellate, Monosiga brevicollis, we compared its PDZ domains with their putative metazoan orthologs. Interestingly, the M. brevicollis genes lack conservation at the classifying positions suggesting dissociation between domain organization in multidomain proteins and specific changes within the PDZ domain.

(c) 2009

Fineberg SK, Kosik KS, Davidson BL. MicroRNAs potentiate neural development.Neuron, 2009 Nov 12;64(3):303-9. Review

MicroRNAs (miRNAs) are endogenously expressed noncoding RNAs that regulate mRNA expression. In vertebrates, more distinct miRNAs are expressed in the brain than in any other tissue, where they are hypothesized to function in neural development. Recent reports describing the effects of specific miRNAs during development, and studies employing miRNA depletion as neural commitment proceeds in the embryo, support a requisite role for miRNAs in cell-fate decisions and provide clues to their function in other aspects of nervous system development.

(c) 2009

Kosik KS. MicroRNAs tell an evo-devo story.

Evolutionary developmental biology, often called evo-devo, seeks to understand the ancestral relationship among organisms by comparing their developmental strategies and ultimately reconstructing the pathways that led to the extraordinary variety of biological forms. The insights from this synthesis of developmental biology and evolutionary principles are useful for understanding the development of the nervous system. The pervasive and crucial roles of microRNAs in nervous system development suggest that these short non-coding transcripts deserve a chapter in the unfolding evo-devo story. The structure of microRNAs, their physical proximity to other genes and their network effects on targets make this class of transcripts tractable genetic material for evolutionary change.

(c) 2009

Papagiannakopoulos T, Kosik KS. MicroRNA-124: Micromanager of Neurogenesis. Cell Stem Cell, 2009 May 8;4(5):375-76

In a recent issue of Nature Neuroscience, Cheng et al. (2009) demonstrate that miR-124, the most abundant of the microRNAs in the adult brain, positively modulates the transitory progression of adult subventricular zone (SVZ) neurogenesis.

(c) 2009

Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS. MicroRNA-145 Regulates OCT4, SOX2, and KLF4 and Represses Pluripotency in Human Embryonic Stem Cells. CELL. 2009 May 15;137

MicroRNAs (miRNAs) are posttranscriptional modulators of gene expression and play an important role in many developmental processes. We report here that expression of microRNA-145 (miR-145) is low in self-renewing human embryonic stem cells (hESCs) but highly upregulated during differentiation. We identify the pluripotency factors OCT4, SOX2, and KLF4 as direct targets of miR-145 and show that endogenous miR-145 represses the 3' untranslated regions of OCT4, SOX2, and KLF4. Increased miR-145 expression inhibits hESC self-renewal, represses expression of pluripotency genes, and induces lineage-restricted differentiation. Loss of miR-145 impairs differentiation and elevates OCT4, SOX2, and KLF4. Furthermore, we find that the miR-145 promoter is bound and repressed by OCT4 in hESCs. This work reveals a direct link between the core reprogramming factors and miR-145 and uncovers a double-negative feedback loop involving OCT4, SOX2, KLF4, and miR-145.

(c) 2009

Carrettiero DC, Hernandez I, Neveu P, Papagiannakopoulos T, Kosik KS. The cochaperone BAG2 sweeps paired helical filament- insoluble tau from the microtubule. J Neurosci. 2009 Feb 18;29(7):2151-6

Tau inclusions are a prominent feature of many neurodegenerative diseases including Alzheimer's disease. Their accumulation in neurons as ubiquitinated filaments suggests a failure in the degradation limb of the Tau pathway. The components of a Tau protein triage system consisting of CHIP/Hsp70 and other chaperones have begun to emerge. However, the site of triage and the master regulatory elements are unknown. Here, we report an elegant mechanism of Tau degradation involving the cochaperone BAG2. The BAG2/Hsp70 complex is tethered to the microtubule and this complex can capture and deliver Tau to the proteasome for ubiquitin-independent degradation. This complex preferentially degrades Sarkosyl insoluble Tau and phosphorylated Tau. BAG2 levels in cells are under the physiological control of the microRNA miR-128a, which can tune paired helical filament Tau levels in neurons. Thus, we propose that ubiquitinated Tau inclusions arise due to shunting of Tau degradation toward a less efficient ubiquitin-dependent pathway.

(c) 2009

Kosik KS. Exploring the early origins of the synapse by comparative genomics. Biol Lett. 2009 Feb 23;5(1):108-11

One set of evolutionary features that has received less attention than the evolution of genes or species is the evolution of cellular machines, the self-contained structures in cells with dedicated functions. Here I suggest that domain expansion through shuffling, duplication, and changes in protein expression level are critical drivers in the evolution of cellular machines. Once established, evolutionary change in these cellular machines tends to occur by paralogy or expansion and modification of the existing core genes. A comparative genomics approach to one cellular machine--the post-synaptic complex--provided preliminary validation of these views. A comparative genomics approach to the entire cellulome may reveal the diversity of cellular machines and their inter-relationships.

(c) 2009

Our neuroscience lab is located on the 5th floor of the Bio2 building just next to the Pacific ocean. We work on neural plasticity including the molecular basis of plasticity, the evolution of synapses, and disease-related impairments of plasticity such as occurs in Alzheimer's disease. Feel free to visit us or send in your comments.