Sidharth V. Puram
Harvard University
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Publication
Featured researches published by Sidharth V. Puram.
Genes & Development | 2008
Núria de la Iglesia; Genevieve Konopka; Sidharth V. Puram; Jennifer A. Chan; Robert M. Bachoo; Mingjian J. You; David E. Levy; Ronald A. DePinho; Azad Bonni
Activation of the transcription factor STAT3 is thought to potently promote oncogenesis in a variety of tissues, leading to intense efforts to develop STAT3 inhibitors for many tumors, including the highly malignant brain tumor glioblastoma. However, the function of STAT3 in glioblastoma pathogenesis has remained unknown. Here, we report that STAT3 plays a pro-oncogenic or tumor-suppressive role depending on the mutational profile of the tumor. Deficiency of the tumor suppressor PTEN triggers a cascade that inhibits STAT3 signaling in murine astrocytes and human glioblastoma tumors. Specifically, we forge a direct link between the PTEN-Akt-FOXO axis and the leukemia inhibitory factor receptor beta (LIFRbeta)-STAT3 signaling pathway. Accordingly, PTEN knockdown induces efficient malignant transformation of astrocytes upon knockout of the STAT3 gene. Remarkably, in contrast to the tumor-suppressive function of STAT3 in the PTEN pathway, STAT3 forms a complex with the oncoprotein epidermal growth factor receptor type III variant (EGFRvIII) in the nucleus and thereby mediates EGFRvIII-induced glial transformation. These findings indicate that STAT3 plays opposing roles in glial transformation depending on the genetic background of the tumor, providing the rationale for tailored therapeutic intervention in glioblastoma.
Cell | 2009
Albert H. Kim; Sidharth V. Puram; Parizad M. Bilimoria; Yoshiho Ikeuchi; Samantha Keough; Michael Wong; David H. Rowitch; Azad Bonni
The ubiquitin ligase anaphase-promoting complex (APC) recruits the coactivator Cdc20 to drive mitosis in cycling cells. However, the nonmitotic functions of Cdc20-APC have remained unexplored. We report that Cdc20-APC plays an essential role in dendrite morphogenesis in postmitotic neurons. Knockdown of Cdc20 in cerebellar slices and in postnatal rats in vivo profoundly impairs the formation of granule neuron dendrite arbors in the cerebellar cortex. Remarkably, Cdc20 is enriched at the centrosome in neurons, and the centrosomal localization is critical for Cdc20-dependent dendrite development. We also find that the centrosome-associated protein histone deacetylase 6 (HDAC6) promotes the polyubiquitination of Cdc20, stimulates the activity of centrosomal Cdc20-APC, and drives the differentiation of dendrites. These findings define a postmitotic function for Cdc20-APC in the morphogenesis of dendrites in the mammalian brain. The identification of a centrosomal Cdc20-APC ubiquitin signaling pathway holds important implications for diverse biological processes, including neuronal connectivity and plasticity.
Proceedings of the National Academy of Sciences of the United States of America | 2007
Elena Choleris; Steven R. Little; Jessica A. Mong; Sidharth V. Puram; Robert Langer; Donald W. Pfaff
Social recognition constitutes the basis of social life. In male mice and rats, social recognition is known to be governed by the neuropeptide oxytocin (OT) through its action on OT receptors (OTRs) in the medial amygdala. In female rats and mice, which have sociosexual behaviors controlling substantial investment in reproduction, an important role for OT in sociosexual behaviors has also been shown. However, the site in the female brain for OT action on social recognition is still unknown. Here we used a customized, controlled release system of biodegradable polymeric microparticles to deliver, in the medial amygdala of female mice, “locked nucleic acid” antisense (AS) oligonucleotides with sequences specific for the mRNA of the OTR gene. We found that single bilateral intraamygdala injections of OTR AS locked nucleic acid oligonucleotides several days before behavioral testing reduced social recognition. Thus, we showed that gene expression for OTR specifically in the amygdala is required for normal social recognition in female mice. Importantly, during the same experiment, we performed a detailed ethological analysis of mouse behavior revealing that OTR AS-treated mice underwent an initial increase in ambivalent risk-assessment behavior. Other behaviors were not affected, thus revealing specific roles for amygdala OTR in female social recognition potentially mediated by anxiety in a social context. Understanding the functional genomics of OT and OTR in social recognition should help elucidate the neurobiological bases of human disorders of social behavior (e.g., autism).
Current Molecular Medicine | 2009
Núria de la Iglesia; Sidharth V. Puram; Azad Bonni
Malignant gliomas are the most common primary brain tumors. Despite efforts to find effective treatments, these tumors remain incurable. The failure of malignant gliomas to respond to conventional cancer therapies may reflect the unique biology of these tumors, underscoring the need for new approaches in their investigation. Recently, progress has been made in characterization of the molecular pathogenesis of glioblastoma using a developmental neurobiological perspective, by exploring the role of signaling pathways that control the differentiation of neural stem cells along the glial lineage. The transcription factor STAT3, which has an established function in neural stem cell and astrocyte development, has been found to play dual tumor suppressive and oncogenic roles in glial malignancy depending on the mutational profile of the tumor. These findings establish a novel developmental paradigm in the study of glioblastoma pathogenesis and provide the rationale for patient-tailored therapy in the treatment of this devastating disease.
Cell | 2017
Sidharth V. Puram; Itay Tirosh; Anuraag Parikh; Anoop P. Patel; Keren Yizhak; Shawn M. Gillespie; Christopher Rodman; Christina L. Luo; Edmund A. Mroz; Kevin S. Emerick; Daniel G. Deschler; Mark A. Varvares; Ravi Mylvaganam; Orit Rozenblatt-Rosen; James W. Rocco; William C. Faquin; Derrick T. Lin; Aviv Regev; Bradley E. Bernstein
The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of ∼6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined HNSCC subtypes by their malignant and stromal composition and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.
Nature Neuroscience | 2011
Sidharth V. Puram; Albert H. Kim; Yoshiho Ikeuchi; Joshua T. Wilson-Grady; Andreas Merdes; Steven P. Gygi; Azad Bonni
The protein kinase calcium/calmodulin-dependent kinase II (CaMKII) predominantly consists of the α and β isoforms in the brain. Although CaMKIIα functions have been elucidated, the isoform-specific catalytic functions of CaMKIIβ have remained unknown. Using knockdown analyses in primary rat neurons and in the rat cerebellar cortex in vivo, we report that CaMKIIβ operates at the centrosome in a CaMKIIα-independent manner to drive dendrite retraction and pruning. We also find that the targeting protein PCM1 (pericentriolar material 1) localizes CaMKIIβ to the centrosome. Finally, we uncover the E3 ubiquitin ligase Cdc20-APC (cell division cycle 20–anaphase promoting complex) as a centrosomal substrate of CaMKIIβ. CaMKIIβ phosphorylates Cdc20 at Ser51, which induces Cdc20 dispersion from the centrosome, thereby inhibiting centrosomal Cdc20-APC activity and triggering the transition from growth to retraction of dendrites. Our findings define a new, isoform-specific function for CaMKIIβ that regulates ubiquitin signaling at the centrosome and thereby orchestrates dendrite patterning, with important implications for neuronal connectivity in the brain.
Development | 2013
Sidharth V. Puram; Azad Bonni
The proper formation and morphogenesis of dendrites is fundamental to the establishment of neural circuits in the brain. Following cell cycle exit and migration, neurons undergo organized stages of dendrite morphogenesis, which include dendritic arbor growth and elaboration followed by retraction and pruning. Although these developmental stages were characterized over a century ago, molecular regulators of dendrite morphogenesis have only recently been defined. In particular, studies in Drosophila and mammalian neurons have identified numerous cell-intrinsic drivers of dendrite morphogenesis that include transcriptional regulators, cytoskeletal and motor proteins, secretory and endocytic pathways, cell cycle-regulated ubiquitin ligases, and components of other signaling cascades. Here, we review cell-intrinsic drivers of dendrite patterning and discuss how the characterization of such crucial regulators advances our understanding of normal brain development and pathogenesis of diverse cognitive disorders.
Genes & Development | 2011
Sidharth V. Puram; Antonio Riccio; Samir Koirala; Yoshiho Ikeuchi; Albert H. Kim; Gabriel Corfas; Azad Bonni
Transient receptor potential (TRP) channels have been implicated as sensors of diverse stimuli in mature neurons. However, developmental roles for TRP channels in the establishment of neuronal connectivity remain largely unexplored. Here, we identify an essential function for TRPC5, a member of the canonical TRP subfamily, in the regulation of dendrite patterning in the mammalian brain. Strikingly, TRPC5 knockout mice harbor long, highly branched granule neuron dendrites with impaired dendritic claw differentiation in the cerebellar cortex. In vivo RNAi analyses suggest that TRPC5 regulates dendrite morphogenesis in the cerebellar cortex in a cell-autonomous manner. Correlating with impaired dendrite patterning in the cerebellar cortex, behavioral analyses reveal that TRPC5 knockout mice have deficits in gait and motor coordination. Finally, we uncover the molecular basis of TRPC5s function in dendrite patterning. We identify the major protein kinase calcium/calmodulin-dependent kinase II β (CaMKIIβ) as a critical effector of TRPC5 function in neurons. Remarkably, TRPC5 forms a complex specifically with CaMKIIβ, but not the closely related kinase CaMKIIα, and thereby induces the CaMKIIβ-dependent phosphorylation of the ubiquitin ligase Cdc20-APC at the centrosome. Accordingly, centrosomal CaMKIIβ signaling mediates the ability of TRPC5 to regulate dendrite morphogenesis in neurons. Our findings define a novel function for TRPC5 that couples calcium signaling to a ubiquitin ligase pathway at the centrosome and thereby orchestrates dendrite patterning and connectivity in the brain.
Nature Neuroscience | 2016
Arezu Jahani-Asl; Hang Yin; Vahab D. Soleimani; Takrima Haque; H. Artee Luchman; Natasha C. Chang; Marie-Claude Sincennes; Sidharth V. Puram; Andrew M. Scott; Ian A. J. Lorimer; Theodore J. Perkins; Keith L. Ligon; Samuel Weiss; Michael A. Rudnicki; Azad Bonni
EGFRvIII-STAT3 signaling is important in glioblastoma pathogenesis. Here, we identified the cytokine receptor OSMR as a direct target gene of the transcription factor STAT3 in mouse astrocytes and human brain tumor stem cells (BTSCs). We found that OSMR functioned as an essential co-receptor for EGFRvIII. OSMR formed a physical complex with EGFRvIII, and depletion of OSMR impaired EGFRvIII-STAT3 signaling. Conversely, pharmacological inhibition of EGFRvIII phosphorylation inhibited the EGFRvIII-OSMR interaction and activation of STAT3. EGFRvIII-OSMR signaling in tumors operated constitutively, whereas EGFR-OSMR signaling in nontumor cells was synergistically activated by the ligands EGF and OSM. Finally, knockdown of OSMR strongly suppressed cell proliferation and tumor growth of mouse glioblastoma cells and human BTSC xenografts in mice, and prolonged the lifespan of these mice. Our findings identify OSMR as a critical regulator of glioblastoma tumor growth that orchestrates a feed-forward signaling mechanism with EGFRvIII and STAT3 to drive tumorigenesis.
Seminars in Cell & Developmental Biology | 2011
Sidharth V. Puram; Azad Bonni
In recent years, diverse and unexpected neurobiological functions have been uncovered for the major cell cycle-regulated ubiquitin ligase, the anaphase-promoting complex (APC). Functions of the APC in the nervous system range from orchestrating neuronal morphogenesis and synapse development to the regulation of neuronal differentiation, survival, and metabolism. The APC acts together with the coactivating proteins Cdh1 and Cdc20 in neural cells to target specific substrates for ubiquitination and consequent degradation by the proteasome. As we continue to unravel APC functions and mechanisms in neurobiology, these studies should advance our understanding of the molecular mechanisms of neuronal connectivity, with important implications for the study of brain development and disease.