A5041439561- Tuberous Sclerosis Complex Research
- Cellular Mechanics and Interactions
- Genetic and Kidney Cyst Diseases
- Retinal Development and Disorders
- Cell Adhesion Molecules Research
- Polyamine Metabolism and Applications
- Microtubule and mitosis dynamics
- Cellular transport and secretion
- Autophagy in Disease and Therapy
- Dermatology and Skin Diseases
- PI3K/AKT/mTOR signaling in cancer
- Genetics and Neurodevelopmental Disorders
- Photoreceptor and optogenetics research
- Histiocytic Disorders and Treatments
- Protist diversity and phylogeny
- Cardiomyopathy and Myosin Studies
- Kruppel-like factors research
- Amyotrophic Lateral Sclerosis Research
- Advanced biosensing and bioanalysis techniques
- Congenital heart defects research
- Erythrocyte Function and Pathophysiology
- Flavonoids in Medical Research
- Lipid metabolism and disorders
- Metabolism, Diabetes, and Cancer
- Hippo pathway signaling and YAP/TAZ
Biogen (United States)
2025
University of California, San Diego
2023
Harvard University
2009-2021
Boston Children's Hospital
2007-2021
Boston Children's Museum
2008-2015
Harvard University Press
2013
Imaging Center
2011
Boston University
2010
Brigham and Women's Hospital
2005
European Molecular Biology Laboratory
2000-2005
Axon formation is fundamental for brain development and function. TSC1 TSC2 are two genes, mutations in which cause tuberous sclerosis complex (TSC), a disease characterized by tumor predisposition neurological abnormalities including epilepsy, mental retardation, autism. Here we show that Tsc1 Tsc2 have critical functions mammalian axon growth. Overexpression of Tsc1/Tsc2 suppresses formation, whereas lack or function induces ectopic axons vitro the mouse brain. phosphorylated inhibited but...
Neuritogenesis, the first step of neuronal differentiation, takes place as nascent neurites bud from immediate postmitotic soma. Little is known about mechanisms underlying dramatic morphological changes that characterize this event. Here, we show RhoA activity plays a decisive role during neuritogenesis cultured hippocampal neurons by recruiting and activating its specific kinase ROCK, which, in turn, complexes with profilin IIa. We establish previously uncharacterized brain-specific...
RNA aptamers that specifically bind dopamine have been isolated by in vitro selection from a pool of 3.4 × 1014 different molecules. One aptamer (dopa2), which dominated the selected pool, has characterized and binds to affinity column with dissociation constant 2.8 μM. The specificity binding determined studying properties number dopamine-related molecules, showing interaction might be mediated hydroxyl group at position 3 proximal aliphatic chain molecule. domain was initially localized...
Tuberous sclerosis complex (TSC) is a multiorgan genetic disease in which brain involvement causes epilepsy, intellectual disability, and autism. The hallmark pathological finding TSC the cerebral cortical tuber its unique constituent, giant cells. However, an animal model that replicates cells has not yet been described. Here, we report mosaic induction of Tsc1 loss neural progenitor cc Nestin-rtTA + TetOp-cre embryos by doxycycline leads to multiple neurological symptoms, including severe...
Tuberous sclerosis complex (TSC) is a neurogenetic disorder caused by loss-of-function mutations in either the TSC1 or TSC2 genes and frequently results prominent CNS manifestations, including epilepsy, mental retardation, autism spectrum disorder. The TSC1/TSC2 protein plays major role controlling Ser/Thr kinase mammalian target of rapamycin (mTOR), which master regulator synthesis cell growth. In this study, we show that endoplasmic reticulum (ER) stress regulates to limit mTOR activity....
Tuberous sclerosis complex (TSC) is a disorder arising from mutation in the TSC1 or TSC2 gene, characterized by development of hamartomas various organs and neurological manifestations including epilepsy, intellectual disability autism. TSC1/2 protein negatively regulates mammalian target rapamycin 1 (mTORC1) master regulator synthesis, cell growth autophagy. Autophagy cellular quality-control process that sequesters cytosolic material double membrane vesicles called autophagosomes degrades...
Disruption of myelination during development has been implicated in a range neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments white matter integrity. Similarly, mice lacking neuronal Tsc1 have hypomyelination phenotype. However, the mechanisms that underlie these phenotypes remain unknown. In this study, we demonstrate TSC1/2 orchestrates program oligodendrocyte maturation through regulated secretion connective tissue growth...
Profilin 2 (PFN2) is an actin binding protein highly expressed in the brain that participates dynamics. It has been shown vitro and vivo neurons it functions both post-synaptically to shape maintain dendritic arborizations spine density plasticity, as well pre-synaptically regulate vesicle exocytosis. PFN2 was also found complexes with proteins have implicated or are causative of autism spectrum disorder. We employ a genetically engineered knock-out mouse line for Pfn2 we previously...
Profilins are a conserved family of proteins participating in actin dynamics and cell motility. In the mouse, two profilin genes known. Profilin I is expressed universally at high levels, while II mainly brain. Here we describe occurrence mouse isoforms, A B, which derived by alternative splicing. They identical through residue 107 protein, but then have distinct C-terminal sequences. IIA binds to poly-L-proline with affinity similar I. IIB on other hand does not bind for greatly diminished....
Hyperactivation of the mechanistic target rapamycin (mTOR) kinase, as a result loss-of-function mutations in tuberous sclerosis complex 1 (<i>TSC1</i>) or <i>TSC2</i> genes, causes protein synthesis dysregulation, increased cell size, and aberrant neuronal connectivity. Dysregulated synaptic proteins has been implicated pathophysiology autism spectrum disorder (ASD) associated with TSC fragile X syndrome. However, type-specific translational profiles these disease models remain to be...
RNA interference silencing of up to 90% Arp3 protein expression, a major subunit the Arp2/3 complex, proportionately decreases intracellular motility Listeria monocytogenes and actin nucleation activity ascribable complex in mouse embryonic fibroblasts. However, Arp2/3-deficient cells exhibit unimpaired lamellipodial network structure, translational locomotion, spreading, assembly, ruffling responses. In addition, Arp3-silenced expressing neural Wiskott-Aldrich syndrome protein-derived...
Mammalian profilins are abundantly expressed actin monomer-binding proteins, highly conserved with respect to their affinities for G-actin, poly-l-proline, and phosphoinositides. Profilins associate a large number of proline-rich proteins; the physiological significance regulation which is poorly understood. Here we show that profilin 2 associates dynamin 1 via C-terminal domain thereby competes binding SH3 ligands such as endophilin, amphiphysin, Grb2, thus interfering assembly endocytic...
Tuberous sclerosis complex (TSC) is a neurogenetic disorder that leads to elevated mechanistic targeting of rapamycin 1 (mTORC1) activity. Cilia can be affected by mTORC1 signaling, and ciliary deficits are associated with neurodevelopmental disorders. Here, we examine whether neuronal cilia in TSC. We show cortical tubers from TSC patients mutant mouse brains have fewer cilia. Using high-content image-based assays, demonstrate activity inversely correlates ciliation TSC1/2-deficient...
CDKL5 Deficiency Disorder (CDD) is a severe encephalopathy characterized by intractable epilepsy, infantile spasms, and cognitive disabilities. The detrimental CNS manifestations lack of therapeutic interventions represent unmet needs, necessitating identification CDD-dependent phenotypes for in vitro disease modeling testing. Here, we optimized high-content assay to quantify cilia CDKL5-deficient neurons. Our work shows that Cdkl5-knockdown neurons have elongated uncovers cilium lengthening...
Genetic manipulations of dissociated rodent neurons provide translatable in vitro models for disease-driven phenotypes. Cilia are cellular antenna with a role neuronal maturation and function often perturbed neurodevelopmental disorders. Efforts automated imaging these microscopic protrusions crucial given the cilia brain. We developed cell-based assay to monitor rat hippocampal using lentiviral-mediated shRNA-based gene silencing. This optimized platform can be used high-throughput imaging,...