David H Rowitch

University of California, San Francisco, San Francisco, California, United States

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Publications (149)1607.88 Total impact

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    ABSTRACT: Despite its critical importance to global brain function, the postnatal development of the human pons remains poorly understood. In the present study, we first performed MRI-based morphometric analyses of the postnatal human pons (0-18 years;n=6-14/timepoint). Pons volume increased 6-fold from birth to 5 years, followed by continued slower growth throughout childhood. The observed growth was primarily due to expansion of the basis pontis. T2-based MRI analysis suggests that this growth is linked to increased myelination, and histological analysis of myelin basic protein in human postmortem specimens confirmed a dramatic increase in myelination during infancy. Analysis of cellular proliferation revealed many Ki67+ cells during the first 7 months of life, particularly during the first month where proliferation was increased in the basis relative to tegmentum. The majority of proliferative cells in the postnatal pons expressed the transcription factor Olig2, suggesting an oligodendrocyte lineage. The proportion of proliferating cells that were Olig2+ was similar through the first 7 months of life and between basis and tegmentum. The number of Ki67+ cells declined dramatically from birth to 7 months and further decreased by 3 years, with a small number of Ki67+ cells observed throughout childhood. In addition, two populations of vimentin/nestin-expressing cells were identified: a dorsal group near the ventricular surface, which persists throughout childhood, and a parenchymal population that diminishes by 7 months and was not evident later in childhood. Together, our data reveal remarkable postnatal growth in the ventral pons, particularly during infancy when cells are most proliferative and myelination increases. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 02/2015; 523(3). DOI:10.1002/cne.23690 · 3.51 Impact Factor
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    ABSTRACT: Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or Phase I/II clinical trials. This shifts the care of leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, leukodystrophy patients are in need of advanced therapies and if possible, a cure. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular Genetics and Metabolism 02/2015; 114(4). DOI:10.1016/j.ymgme.2015.01.014 · 2.83 Impact Factor
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    ABSTRACT: Astrocytes have many roles within the brain parenchyma, and a subpopulation restricted to germinal niches function as neural stem cells (NSCs), that produce various types of neuronal progeny in relation to spatiotemporal factors. A growing body of evidence supports the concept of morphological and molecular differences between astrocytes in different brain regions, which might relate to their derivation from regionally patterned radial glia. Indeed, the notion that astrocytes are molecularly and functionally heterogeneous could help explain how the central nervous system (CNS) retains embryonic positional information into adulthood. Here, we discuss recent evidence for regionally encoded functions of astrocytes in the developing and adult CNS to provide an integrated concept of the origin and possible function of astrocyte heterogeneity. We focus on the regionalization of NSCs in the ventricular-subventricular zone (V-SVZ) of the adult mammalian brain and emerging evidence for a segmental organization of astrocytes in the developing spinal cord and forebrain. We propose that astrocytes' diversity will provide fundamental clues to understand regional brain organization and function. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 11/2014; 7(1). DOI:10.1101/cshperspect.a020362 · 8.23 Impact Factor
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    ABSTRACT: Myelin sheaths provide critical functional and trophic support for axons in white matter tracts of the brain. Oligodendrocyte precursor cells (OPCs) have extraordinary metabolic requirements during development as they differentiate to produce multiple myelin segments, implying that they must first secure adequate access to blood supply. However, mechanisms that coordinate myelination and angiogenesis are unclear. Here, we show that oxygen tension, mediated by OPC-encoded hypoxia-inducible factor (HIF) function, is an essential regulator of postnatal myelination. Constitutive HIF1/2α stabilization resulted in OPC maturation arrest through autocrine activation of canonical Wnt7a/7b. Surprisingly, such OPCs also show paracrine activity that induces excessive postnatal white matter angiogenesis in vivo and directly stimulates endothelial cell proliferation in vitro. Conversely, OPC-specific HIF1/2α loss of function leads to insufficient angiogenesis in corpus callosum and catastrophic axon loss. These findings indicate that OPC-intrinsic HIF signaling couples postnatal white matter angiogenesis, axon integrity, and the onset of myelination in mammalian forebrain.
    Cell 07/2014; 158(2). DOI:10.1016/j.cell.2014.04.052 · 33.12 Impact Factor
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    ABSTRACT: Hypomyelinating leukodystrophies represent a genetically heterogeneous but clinically overlapping group of heritable disorders. Current management approaches in the care of the patient with a hypomyelinating leukodystrophy include use of serial MR imaging to establish and monitor hypomyelination, molecular diagnostics to determine a specific etiology, and, equally important, careful attention to neurologic complications over time. Emerging research in oligodendrocyte biology and neuroradiology with bedside applications may result in the possibility of clinical trials in the near term, yet there are significant gaps in knowledge in disease classification, characterization and outcome measures in this group of disorders. Here we review the biological background of myelination, the clinical and genetic variability in hypomyelinating leukodystrophies, and the insights that can be obtained from current MRI techniques. In addition, we discuss ongoing research approaches to define potential outcome markers for future clinical trials. ANN NEUROL 2014. © 2014 American Neurological Association.
    Annals of Neurology 07/2014; 76(1). DOI:10.1002/ana.24194 · 11.91 Impact Factor
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    ABSTRACT: The bHLH transcription factor Olig2 is expressed in cycling neural progenitor cells but also in terminally differentiated, myelinating oligodendrocytes. Sustained expression of Olig2 is counterintuitive because all known functions of the protein in expansion of neural progenitors and specification of oligodendrocyte progenitors are completed with the formation of mature white matter. How are the biological functions of Olig2 suppressed in terminally differentiated oligodendrocytes? In previous studies, we have shown that a triple serine motif in the amino terminus of Olig2 is phosphorylated in cycling neural progenitors but not in their differentiated progeny. We now show that phosphorylation of the triple serine motif regulates intranuclear compartmentalization of murine Olig2. Phosphorylated Olig2 is preferentially localized to a transcriptionally active "open" chromatin compartment together with coregulator proteins essential for regulation of gene expression. Unphosphorylated Olig2, as seen in mature white matter, is localized mainly within a transcriptionally inactive, chromatin fraction characterized by condensed and inaccessible DNA. Of special note is the observation that the p53 tumor suppressor protein is confined to the open chromatin fraction. Proximity ligation assays show that phosphorylation brings Olig2 within 30 nm of p53 within the open chromatin compartment. The data thus shed light on previously noted promitogenic functions of phosphorylated Olig2, which reflect, at least in part, an oppositional relationship with p53 functions.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2014; 34(25):8507-18. DOI:10.1523/JNEUROSCI.0309-14.2014 · 6.75 Impact Factor
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    ABSTRACT: Astrocytes, the most abundant cells in the central nervous system, promote synapse formation and help to refine neural connectivity. Although they are allocated to spatially distinct regional domains during development, it is unknown whether region-restricted astrocytes are functionally heterogeneous. Here we show that postnatal spinal cord astrocytes express several region-specific genes, and that ventral astrocyte-encoded semaphorin 3a (Sema3a) is required for proper motor neuron and sensory neuron circuit organization. Loss of astrocyte-encoded Sema3a leads to dysregulated α-motor neuron axon initial segment orientation, markedly abnormal synaptic inputs, and selective death of α- but not of adjacent γ-motor neurons. In addition, a subset of TrkA(+) sensory afferents projects to ectopic ventral positions. These findings demonstrate that stable maintenance of a positional cue by developing astrocytes influences multiple aspects of sensorimotor circuit formation. More generally, they suggest that regional astrocyte heterogeneity may help to coordinate postnatal neural circuit refinement.
    Nature 04/2014; 509(7499). DOI:10.1038/nature13161 · 42.35 Impact Factor
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    ABSTRACT: In colon cancer, mutation of the Wnt repressor APC (encoding adenomatous polyposis coli) leads to a state of aberrant and unrestricted high-activity signaling. However, the relevance of high Wnt tone in non-genetic human disease is unknown. Here we demonstrate that distinct functional states of Wnt activity determine oligodendrocyte precursor cell (OPC) differentiation and myelination. Mouse OPCs with genetic Wnt dysregulation (high tone) express multiple genes in common with colon cancer, including Lef1, Sp5, Ets2, Rnf43 and Dusp4. Surprisingly, we found that OPCs in lesions of hypoxic human neonatal white matter injury upregulated markers of high Wnt activity and lacked expression of APC. We also found that lack of Wnt repressor tone promoted permanent white matter injury after mild hypoxic insult. These findings suggest a state of pathological high-activity Wnt signaling in human disease tissues that lack predisposing genetic mutation.
    Nature Neuroscience 03/2014; DOI:10.1038/nn.3676 · 14.98 Impact Factor
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    ABSTRACT: Abnormal GABAergic interneuron density, and imbalance of excitatory versus inhibitory tone, is thought to result in epilepsy, neurodevelopmental disorders, and psychiatric disease. Recent studies indicate that interneuron cortical density is determined primarily by the size of the precursor pool in the embryonic telencephalon. However, factors essential for regulating interneuron allocation from telencephalic multipotent precursors are poorly understood. Here we report that Olig1 represses production of GABAergic interneurons throughout the mouse brain. Olig1 deletion in mutant mice results in ectopic expression and upregulation of Dlx1/2 genes in the ventral medial ganglionic eminences and adjacent regions of the septum, resulting in an ∼30% increase in adult cortical interneuron numbers. We show that Olig1 directly represses the Dlx1/2 I12b intergenic enhancer and that Dlx1/2 functions genetically downstream of Olig1. These findings establish Olig1 as an essential repressor of Dlx1/2 and interneuron production in developing mammalian brain.
    Neuron 02/2014; 81(3):574-87. DOI:10.1016/j.neuron.2013.11.024 · 15.98 Impact Factor
  • Marc R Freeman, David H Rowitch
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    ABSTRACT: Glial cells are present in all organisms with a CNS and, with increasing brain complexity, glial cells have undergone substantive increases in cell number, diversity, and functions. Invertebrates, such as Drosophila, possess glial subtypes with similarity to mammalian astrocytes in their basic morphology and function, representing fertile ground for unraveling fundamental aspects of glial biology. Although glial subtypes in simple organisms may be relatively homogenous, emerging evidence suggests the possibility that mammalian astrocytes might be highly diversified to match the needs of local neuronal subtypes. In this Perspective, we review classic and new roles identified for astrocytes and oligodendrocytes by recent studies. We propose that delineating genetic and developmental programs across species will be essential to understand the core functions of glia that allow enhanced neuronal function and to achieve new insights into glial roles in higher-order brain function and neurological disease.
    Neuron 10/2013; 80(3):613-23. DOI:10.1016/j.neuron.2013.10.034 · 15.98 Impact Factor
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    ABSTRACT: The mammalian genome encodes two A-type cyclins, which are considered potentially redundant yet essential regulators of the cell cycle. Here, we tested requirements for cyclin A1 and cyclin A2 function in cerebellar development. Compound conditional loss of cyclin A1/A2 in neural progenitors resulted in severe cerebellar hypoplasia, decreased proliferation of cerebellar granule neuron progenitors (CGNP), and Purkinje (PC) neuron dyslamination. Deletion of cyclin A2 alone showed an identical phenotype, demonstrating that cyclin A1 does not compensate for cyclin A2 loss in neural progenitors. Cyclin A2 loss lead to increased apoptosis at early embryonic time points but not at post-natal time points. In contrast, neural progenitors of the VZ/SVZ did not undergo increased apoptosis, indicating that VZ/SVZ-derived and rhombic lip-derived progenitor cells show differential requirements to cyclin A2. Conditional knockout of cyclin A2 or the SHH proliferative target Nmyc in CGNP also resulted in PC neuron dyslamination. Although cyclin E1 has been reported to compensate for cyclin A2 function in fibroblasts and is upregulated in cyclin A2 null cerebella, cyclin E1 expression was unable to compensate for loss-of cyclin A2 function.
    Developmental Biology 10/2013; 385(2). DOI:10.1016/j.ydbio.2013.10.019 · 3.64 Impact Factor
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    ABSTRACT: Midbrain- and hindbrain-derived GABAergic interneurons are critical for regulation of sleep, respiratory, sensory-motor and motivational processes, and they are implicated in human neurological disorders. However, the precise mechanisms that underlie generation of GABAergic neuron diversity in the midbrain-hindbrain region are poorly understood. Here, we show unique and overlapping requirements for the related bHLH proteins Tal1 and Tal2 in GABAergic neurogenesis in the midbrain. We show that Tal2 and Tal1 are specifically and sequentially activated during midbrain GABAergic neurogenesis. Similar to Gata2, a post-mitotic selector of the midbrain GABAergic neuron identity, Tal2 expression is activated very early during GABAergic neuron differentiation. Although the expression of Tal2 and Gata2 genes are independent of each other, Tal2 is important for normal midbrain GABAergic neurogenesis, possibly as a partner of Gata2. In the absence of Tal2, the majority of midbrain GABAergic neurons switch to a glutamatergic-like phenotype. In contrast, Tal1 expression is activated in a Gata2 and Tal2 dependent fashion in the more mature midbrain GABAergic neuron precursors, but Tal1 alone is not required for GABAergic neuron differentiation from the midbrain neuroepithelium. However, inactivation of both Tal2 and Tal1 in the developing midbrain suggests that the two factors co-operate to guide GABAergic neuron differentiation in a specific ventro-lateral midbrain domain. The observed similarities and differences between Tal1/Tal2 and Gata2 mutants suggest both co-operative and unique roles for these factors in determination of midbrain GABAergic neuron identities.
    10/2013; 2(10):990-7. DOI:10.1242/bio.20135041
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    ABSTRACT: Developmental regulation of gliogenesis in the mammalian CNS is incompletely understood, in part due to a limited repertoire of lineage-specific genes. We used Aldh1l1-GFP as a marker for gliogenic radial glia and later-stage precursors of developing astrocytes and performed gene expression profiling of these cells. We then used this dataset to identify candidate transcription factors that may serve as glial markers or regulators of glial fate. Our analysis generated a database of developmental stage-related markers of Aldh1l1+ cells between murine embryonic day 13.5-18.5. Using these data we identify the bZIP transcription factor Nfe2l1 and demonstrate that it promotes glial fate under direct Sox9 regulatory control. Thus, this dataset represents a resource for identifying novel regulators of glial development. GLIA 2013.
    Glia 09/2013; 61(9). DOI:10.1002/glia.22538 · 5.47 Impact Factor
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    ABSTRACT: The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2013; 33(33):13460-13474. DOI:10.1523/JNEUROSCI.1333-13.2013 · 6.75 Impact Factor
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    ABSTRACT: Cellular stress responses are frequently governed by the subcellular localization of critical effector proteins. Apoptosis-inducing Factor (AIF) or Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH), for example, can translocate from mitochondria to the nucleus, where they modulate apoptotic death pathways. Hypoxia-inducible gene domain 1A (HIGD1A) is a mitochondrial protein regulated by Hypoxia-inducible Factor-1α (HIF1α). Here we show that while HIGD1A resides in mitochondria during physiological hypoxia, severe metabolic stress, such as glucose starvation coupled with hypoxia, in addition to DNA damage induced by etoposide, triggers its nuclear accumulation. We show that nuclear localization of HIGD1A overlaps with that of AIF, and is dependent on the presence of BAX and BAK. Furthermore, we show that AIF and HIGD1A physically interact. Additionally, we demonstrate that nuclear HIGD1A is a potential marker of metabolic stress in vivo, frequently observed in diverse pathological states such as myocardial infarction, hypoxic-ischemic encephalopathy (HIE), and different types of cancer. In summary, we demonstrate a novel nuclear localization of HIGD1A that is commonly observed in human disease processes in vivo.
    PLoS ONE 04/2013; 8(4):e62758. DOI:10.1371/journal.pone.0062758 · 3.53 Impact Factor
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    ABSTRACT: Krabbe disease is a devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. A significant subset of the infantile form of the disease is due to missense mutations that result in aberrant protein production. The currently used mouse model, twitcher, has a nonsense mutation not found in Krabbe patients, although it is similar to the human 30kb deletion in abrogating GALC expression. Here, we identify a spontaneous mutation in GALC, GALC(twi-5J), that precisely matches the E130 K missense mutation in patients with infantile Krabbe disease. GALC(twi-5J) homozygotes show loss of enzymatic activity despite normal levels of precursor protein, and manifest a more severe phenotype than twitcher, with half the life span. Although neuropathological hallmarks such as gliosis, globoid cells, and psychosine accumulation are present throughout the nervous system, the CNS does not manifest significant demyelination. In contrast, the PNS is severely hypomyelinated and lacks large diameter axons, suggesting primary dysmyelination, rather than a demyelinating process. Our data indicate that early demise is due to mechanisms other than myelin loss and support an important role for neuroinflammation in Krabbe disease progression. Furthermore, our results argue against a causative relationship between psychosine accumulation, white matter loss, and gliosis.
    Human Molecular Genetics 04/2013; DOI:10.1093/hmg/ddt190 · 6.68 Impact Factor
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    ABSTRACT: OBJECTIVE: Pathological findings in neonatal brain injury associated with preterm birth include focal and/or diffuse white matter injury (WMI). Despite the heterogeneous nature of this condition, reactive astrogliosis and microgliosis are frequently observed. Thus, molecular mechanisms by which glia activation contribute to WMI were investigated. METHODS: Postmortem brains of neonatal brain injury were investigated to identify molecular features of reactive astrocytes. The contribution of astrogliosis to WMI was further tested in a mouse model in genetically engineered mice. RESULTS: Activated STAT3 signaling in reactive astrocytes was found to be a common feature in postmortem brains of neonatal brain injury. In a mouse model of neonatal WMI, conditional deletion of STAT3 in astrocytes resulted in exacerbated WMI, which was associated with delayed maturation of oligodendrocytes. Mechanistically, the delay occurred in association with overexpression of transforming growth factor (TGF)β-1 in microglia, which in healthy controls decreased with myelin maturation in an age-dependent manner. TGFβ-1 directly and dose-dependently inhibited the maturation of purified oligodendrocyte progenitors, and pharmacological inhibition of TGFβ-1 signaling in vivo reversed the delay in myelin development. Factors secreted from STAT3-deficient astrocytes promoted elevated TGFβ-1 production in cultured microglia compared to wild-type astrocytes. INTERPRETATION: These results suggest that myelin development is regulated by a mechanism involving crosstalk between microglia and oligodendrocyte progenitors. Reactive astrocytes may modify this signaling in a STAT3-dependent manner, preventing the pathological expression of TGFβ-1 in microglia and the impairment of oligodendrocyte maturation. ANN NEUROL 2012;
    Annals of Neurology 11/2012; 72(5). DOI:10.1002/ana.23670 · 11.91 Impact Factor
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    ABSTRACT: The basic helix-loop-helix transcription factors oligodendrocyte transcription factor 1 (OLIG1) and OLIG2 are structurally similar and, to a first approximation, coordinately expressed in the developing CNS and postnatal brain. Despite these similarities, it was apparent from early on after their discovery that OLIG1 and OLIG2 have non-overlapping developmental functions in patterning, neuron subtype specification and the formation of oligodendrocytes. Here, we summarize more recent insights into the separate roles of these transcription factors in the postnatal brain during repair processes and in neurological disease states, including multiple sclerosis and malignant glioma. We discuss how the unique functions of OLIG1 and OLIG2 may reflect their distinct genetic targets, co-regulator proteins and/or post-translational modifications.
    Nature Reviews Neuroscience 11/2012; 13(12):819-31. DOI:10.1038/nrn3386 · 31.38 Impact Factor
  • Immunobiology 11/2012; 217(11):1133. DOI:10.1016/j.imbio.2012.08.014 · 3.18 Impact Factor

Publication Stats

14k Citations
1,607.88 Total Impact Points


  • 2007–2015
    • University of California, San Francisco
      • • Department of Neurological Surgery
      • • Department of Pediatrics
      San Francisco, California, United States
  • 2014
    • Fachkrankenhaus Hubertusburg gGmbH
      Leipzig, Saxony, Germany
  • 2008–2014
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 2013
    • Oregon Health and Science University
      • Department of Pediatrics
      Los Angeles, CA, United States
  • 2001–2012
    • Dana-Farber Cancer Institute
      • • Department of Cancer Biology
      • • Department of Pediatric Oncology
      Boston, MA, United States
  • 2011
    • CSU Mentor
      Long Beach, California, United States
  • 1995–2007
    • Harvard University
      • • Department of Molecular and Cell Biology
      • • Department of Developmental Biology
      Cambridge, Massachusetts, United States
  • 1997–2006
    • Harvard Medical School
      • Department of Pediatrics
      Boston, Massachusetts, United States