David Rowitch

Last updated
David Rowitch

FMedSci FRS
Born
USA
Education
Known for
  • Genetics of glia differentiation
  • First Neuro – NICU
Scientific career
Fields
Institutions
Thesis Structure and assembly of filamentous bacteriophages  (1988)
Doctoral advisor Richard Perham
Other academic advisorsAndy McMahon
Notable students Anna Molofsky
Website rowitchlab.medschl.cam.ac.uk

David Rowitch, FMedSci, FRS is an American physician-scientist known for his contributions to developmental glial biology and treatment of white matter diseases. He heads the Department of Paediatrics at the University of Cambridge and is an adjunct professor of pediatrics at the University of California San Francisco (UCSF).

Contents

Education and career

Rowitch earned a BA in cell biology from University of California San Diego in 1982. [1] He received his PhD in biochemistry in 1988 from the University of Cambridge, where he worked with Richard Perham on filamentous bacteriophages; [2] and his MD from University of California Los Angeles in 1989. Following the completion of his degrees, Rowitch trained in pediatrics (1989–92) and neonatal-perinatal medicine (1993–96) at Boston Children's Hospital. He conducted research with Andrew P. McMahon as a postdoctoral fellow at Harvard University from 1994 to 1998. [1]

In 1999, Rowitch joined the faculty of Harvard Medical School as an assistant professor of pediatrics and established his laboratory at Dana–Farber Cancer Institute, where he led foundational work on the genetics of neuron and glia differentiation. [3] He was promoted to associate professor in 2004. [1]

Rowitch departed HMS in 2006, moving to San Francisco to become the Chief of Neonatology at UCSF Benioff Children's Hospital. [4] There, he helped to lead the formation of the first neonatal intensive care unit specializing in neurointensive care for premature infants. [4] [5] He continued to conduct research and was named an HHMI Investigator in 2007. [6]

In 2016, Rowitch became the head of the Department of Paediatrics and was awarded an honorary ScD at the University of Cambridge. [7] Rowitch was appointed a Wellcome Trust Senior Investigator at the Wellcome–MRC Cambridge Stem Cell Institute. He retained an adjunct professorship of pediatrics and neurosurgery at UCSF, where he continues to have a lab in the Eli and Edyth Broad Institute for Stem Cell Research and Regenerative Medicine. [1] He is a co-principal investigator of the Autism Prenatal Sex Differences (APEX) study funded by the Simons Foundation Autism Research Initiative in 2021. [8] He returned to the San Francisco Bay Area in late 2023.

Research

Broadly, Rowitch studies the specification of oligodendrocytes and astrocytes in the central nervous system. His work has spanned normal development as well as multiple disease areas, especially those impacting white matter such as cerebral palsy, leukodystrophy, and multiple sclerosis. [1]

His laboratory was the first to isolate Olig1 and Olig2, [9] two related bHLH transcription factors which are essential for the differentiation of both motoneurons and oligodendrocytes. [10] [11] Subsequent work from his group demonstrated that Olig2 is also present in diffuse gliomas, [12] suggesting that primary brain tumor progression can share molecular mechanisms with normal neurodevelopment, such as Sonic hedgehog signaling. [3] [13] Rowitch also led or co-led high-throughput screens to identify candidate genes related to neuron and glia specification, including a genome-wide library of transcription factors involved in mouse brain organization [14] and microarray-based gene expression profiling of astrocyte-specific genes. [15]

His laboratory has helped to establish the importance of oligodendrocyte progenitor cells in promoting postnatal angiogenesis in white matter by delaying myelination until the appropriate developmental time via hypoxia-inducible factor activity and canonical Wnt signaling. [16] [17]

Rowitch was the primary investigator of a first-in-human clinical trial funded by StemCells, Inc. to transplant neural stem cells directly into the brains of patients with Pelizaeus-Merzbacher disease (PMD). [18] Dermal fibroblasts donated by the patients were also studied to reveal that iron toxicity is primarily responsible for oligodendrocyte death in early-onset PMD, and that treatment with deferiprone could rescue myelination in vitro and in mice. [19]

Awards and honors

Rowitch was elected to the Association of American Physicians in 2012, [1] the Academy of Medical Sciences in 2018, [20] and the Royal Society in 2021. [21] He was appointed to the National Advisory Child Health and Human Development Council in 2020. [1] [22]

Related Research Articles

<span class="mw-page-title-main">Myelin</span> Fatty substance that surrounds nerve cell axons to insulate them and increase transmission speed

In vertebrates, most neuronal cell axons are encased in myelin. Simply put, myelin insulates axons and increases the rate at which electrical impulses are passed along the axon. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, myelin ensheaths the axon in segments: in general, each axon is encased in multiple long myelin sheaths separated by short gaps called nodes of Ranvier.

<span class="mw-page-title-main">Schwann cell</span> Glial cell type

Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.

<span class="mw-page-title-main">Nervous tissue</span> Main component of the nervous system

Nervous tissue, also called neural tissue, is the main tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) comprising the brain and spinal cord, and the peripheral nervous system (PNS) comprising the branching peripheral nerves. It is composed of neurons, also known as nerve cells, which receive and transmit impulses, and neuroglia, also known as glial cells or glia, which assist the propagation of the nerve impulse as well as provide nutrients to the neurons.

<span class="mw-page-title-main">Oligodendrocyte</span> Neural cell type

Oligodendrocytes, also known as oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons within the central nervous system (CNS) of jawed vertebrates. Their function is similar to that of Schwann cells, which perform the same task in the peripheral nervous system (PNS). Oligodendrocytes accomplish this by forming the myelin sheath around axons. Unlike Schwann cells, a single oligodendrocyte can extend its processes to cover around 50 axons, with each axon being wrapped in approximately 1 μm of myelin sheath. Furthermore, an oligodendrocyte can provide myelin segments for multiple adjacent axons.

<span class="mw-page-title-main">Glia</span> Support cells in the nervous system

Glia, also called glial cells(gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. The neuroglia make up more than one half the volume of neural tissue in our body. They maintain homeostasis, form myelin in the peripheral nervous system, and provide support and protection for neurons. In the central nervous system, glial cells include oligodendrocytes, astrocytes, ependymal cells and microglia, and in the peripheral nervous system they include Schwann cells and satellite cells.

<span class="mw-page-title-main">Astrocyte</span> Type of brain cell

Astrocytes, also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endothelial cells that form the blood–brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, regulation of cerebral blood flow, and a role in the repair and scarring process of the brain and spinal cord following infection and traumatic injuries. The proportion of astrocytes in the brain is not well defined; depending on the counting technique used, studies have found that the astrocyte proportion varies by region and ranges from 20% to around 40% of all glia. Another study reports that astrocytes are the most numerous cell type in the brain. Astrocytes are the major source of cholesterol in the central nervous system. Apolipoprotein E transports cholesterol from astrocytes to neurons and other glial cells, regulating cell signaling in the brain. Astrocytes in humans are more than twenty times larger than in rodent brains, and make contact with more than ten times the number of synapses.

Oligodendrocyte progenitor cells (OPCs), also known as oligodendrocyte precursor cells, NG2-glia, O2A cells, or polydendrocytes, are a subtype of glia in the central nervous system named for their essential role as precursors to oligodendrocytes. They are typically identified in the human by co-expression of PDGFRA and CSPG4.

<span class="mw-page-title-main">Radial glial cell</span> Bipolar-shaped progenitor cells of all neurons in the cerebral cortex and some glia

Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system.

<span class="mw-page-title-main">Subventricular zone</span> Region outside each lateral ventricle of the brain

The subventricular zone (SVZ) is a region situated on the outside wall of each lateral ventricle of the vertebrate brain. It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative zone containing neural progenitor cells, which divide to produce neurons in the process of neurogenesis. The primary neural stem cells of the brain and spinal cord, termed radial glial cells, instead reside in the ventricular zone (VZ).

Remyelination is the process of propagating oligodendrocyte precursor cells to form oligodendrocytes to create new myelin sheaths on demyelinated axons in the CNS. This is a process naturally regulated in the body and tends to be very efficient in a healthy CNS. The process creates a thinner myelin sheath than normal, but it helps to protect the axon from further damage, from overall degeneration, and proves to increase conductance once again. The processes underlying remyelination are under investigation in the hope of finding treatments for demyelinating diseases, such as multiple sclerosis.

A nerve guidance conduit is an artificial means of guiding axonal regrowth to facilitate nerve regeneration and is one of several clinical treatments for nerve injuries. When direct suturing of the two stumps of a severed nerve cannot be accomplished without tension, the standard clinical treatment for peripheral nerve injuries is autologous nerve grafting. Due to the limited availability of donor tissue and functional recovery in autologous nerve grafting, neural tissue engineering research has focused on the development of bioartificial nerve guidance conduits as an alternative treatment, especially for large defects. Similar techniques are also being explored for nerve repair in the spinal cord but nerve regeneration in the central nervous system poses a greater challenge because its axons do not regenerate appreciably in their native environment.

Myelinogenesis is the formation and development of myelin sheaths in the nervous system, typically initiated in late prenatal neurodevelopment and continuing throughout postnatal development. Myelinogenesis continues throughout the lifespan to support learning and memory via neural circuit plasticity as well as remyelination following injury. Successful myelination of axons increases action potential speed by enabling saltatory conduction, which is essential for timely signal conduction between spatially separate brain regions, as well as provides metabolic support to neurons.

<span class="mw-page-title-main">OLIG2</span> Protein-coding gene in the species Homo sapiens

Oligodendrocyte transcription factor (OLIG2) is a basic helix-loop-helix (bHLH) transcription factor encoded by the OLIG2 gene. The protein is of 329 amino acids in length, 32 kDa in size and contains one basic helix-loop-helix DNA-binding domain. It is one of the three members of the bHLH family. The other two members are OLIG1 and OLIG3. The expression of OLIG2 is mostly restricted in central nervous system, where it acts as both an anti-neurigenic and a neurigenic factor at different stages of development. OLIG2 is well known for determining motor neuron and oligodendrocyte differentiation, as well as its role in sustaining replication in early development. It is mainly involved in diseases such as brain tumor and Down syndrome.

<span class="mw-page-title-main">OLIG1</span> Protein-coding gene in the species Homo sapiens

Oligodendrocyte transcription factor 1 is a protein that in humans is encoded by the OLIG1 gene.

<span class="mw-page-title-main">Myelin regulatory factor</span> Mammalian protein found in Homo sapiens

Myelin regulatory factor, also known as myelin gene regulatory factor (MRF), is a protein that in humans is encoded by the MYRF gene.

<span class="mw-page-title-main">Neuronal lineage marker</span> Endogenous tag expressed in different cells along neurogenesis and differentiated cells

A neuronal lineage marker is an endogenous tag that is expressed in different cells along neurogenesis and differentiated cells such as neurons. It allows detection and identification of cells by using different techniques. A neuronal lineage marker can be either DNA, mRNA or RNA expressed in a cell of interest. It can also be a protein tag, as a partial protein, a protein or an epitope that discriminates between different cell types or different states of a common cell. An ideal marker is specific to a given cell type in normal conditions and/or during injury. Cell markers are very valuable tools for examining the function of cells in normal conditions as well as during disease. The discovery of various proteins specific to certain cells led to the production of cell-type-specific antibodies that have been used to identify cells.

Patrizia Casaccia is an Italian neuroscientist who is the Director of the Neuroscience Initiative of the Advanced Science Research Center at the City University of New York (CUNY), as well as a Professor of Neuroscience, Genetics & Genomics, and Neurology at the Icahn School of Medicine at Mount Sinai. Casaccia is a pioneer in the study of myelin and her research focuses on understanding the neurobiological and neuroimmune mechanisms of multiple sclerosis to translate their findings into treatments. Casaccia co-founded the Center for Glial Biology at Mount Sinai and CUNY and is one of the Directors of the center.

<span class="mw-page-title-main">Brain cell</span> Functional tissue of the brain

Brain cells make up the functional tissue of the brain. The rest of the brain tissue is structural or connective called the stroma which includes blood vessels. The two main types of cells in the brain are neurons, also known as nerve cells, and glial cells, also known as neuroglia.

Valentina Fossati is an Italian stem cell biologist. She is a Senior Research Investigator at the New York Stem Cell Foundation. Her research is focused on developing human stem cell-based models to study the role of glia in neurodegeneration and neuroinflammation.

Myelinoids or myelin organoids are three dimensional in vitro cultured model derived from human pluripotent stem cells (hPSCs) that represent various brain regions, spinal cord or the peripheral nervous system in early fetal human development. They have the capacity to recapitulate aspects of brain developmental processes, microenvironments, cell to cell interaction, structural organization and cellular composition. The differentiating aspect dictating whether an organoid is deemed a cerebral organoid/brain organoid or myelinoid is the presence of myelination and compact myelin formation that is a defining feature of myelinoids. Due to the complex nature of the human brain, there is a need for model systems which can closely mimic complicated biological processes. Myelinoids provide a unique in vitro model through which myelin pathology, neurodegenerative diseases, developmental processes and therapeutic screening can be accomplished.

References

  1. 1 2 3 4 5 6 7 "David Rowitch, MD, PhD". UCSF Profiles. Retrieved 2021-09-30.
  2. ↑ Berry A, Radford SE (29 August 2018). "Richard Nelson Perham. 27 April 1937—14 February 2015". Biogr Mem Fellows R Soc. The Royal Society. 65: 317–339. doi: 10.1098/rsbm.2018.0004 . S2CID   81280537.
  3. 1 2 "Childhood brain tumor traced to normal stem cells gone bad". Dana–Farber Cancer Institute. 12 August 2008. Retrieved 2021-09-30.
  4. 1 2 "Envisioning a Neuro ICU for Preemies at UCSF". UCSF. 11 July 2006. Retrieved 2021-09-30.
  5. ↑ Brown, Phyllis (14 May 2007). "New Clinical Director Envisions "Fully Connected" Intensive Care Nursery". UCSF. Retrieved 2021-09-30.
  6. ↑ "UCSF's Rowitch Selected as Howard Hughes Medical Institute Patient-Oriented Research Investigator". UCSF. Retrieved 2021-09-30.
  7. ↑ "Cambridge Stem Cell Institute Annual Review 2016". University of Cambridge. 28 February 2017. p. 7. Retrieved 2021-09-30.
  8. ↑ "2020 SFARI Collaboration on Sex Differences in Autism awardees announced". Simons Foundation. 29 July 2021. Retrieved 2021-09-30.
  9. ↑ Lu QR, Yuk D, Alberta JA, Zhu Z, Pawlitzky I, Chan J; et al. (2000). "Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system". Neuron. 25 (2): 317–29. doi: 10.1016/s0896-6273(00)80897-1 . PMID   10719888. S2CID   14558569.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ↑ Lu QR, Sun T, Zhu Z, Ma N, Garcia M, Stiles CD; et al. (2002). "Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection". Cell. 109 (1): 75–86. doi: 10.1016/s0092-8674(02)00678-5 . PMID   11955448. S2CID   1865925.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ↑ Ligon KL, Kesari S, Kitada M, Sun T, Arnett HA, Alberta JA; et al. (2006). "Development of NG2 neural progenitor cells requires Olig gene function". Proc Natl Acad Sci U S A. 103 (20): 7853–8. Bibcode:2006PNAS..103.7853L. doi: 10.1073/pnas.0511001103 . PMC   1472534 . PMID   16682644.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ↑ Ligon KL, Alberta JA, Kho AT, Weiss J, Kwaan MR, Nutt CL; et al. (2004). "The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas". J Neuropathol Exp Neurol. 63 (5): 499–509. doi:10.1093/jnen/63.5.499. PMID   15198128.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ↑ Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK; et al. (2001). "Malignant glioma: genetics and biology of a grave matter". Genes Dev. 15 (11): 1311–33. doi: 10.1101/gad.891601 . PMID   11390353. S2CID   19359819.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ↑ Gray PA, Fu H, Luo P, Zhao Q, Yu J, Ferrari A; et al. (2004). "Mouse brain organization revealed through direct genome-scale TF expression analysis". Science. 306 (5705): 2255–7. Bibcode:2004Sci...306.2255G. doi:10.1126/science.1104935. PMID   15618518. S2CID   43092315.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ↑ Bachoo RM, Kim RS, Ligon KL, Maher EA, Brennan C, Billings N; et al. (2004). "Molecular diversity of astrocytes with implications for neurological disorders". Proc Natl Acad Sci U S A. 101 (22): 8384–9. Bibcode:2004PNAS..101.8384B. doi: 10.1073/pnas.0402140101 . PMC   420403 . PMID   15155908.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ↑ Yuen TJ, Silbereis JC, Griveau A, Chang SM, Daneman R, Fancy SPJ; et al. (2014). "Oligodendrocyte-encoded HIF function couples postnatal myelination and white matter angiogenesis". Cell. 158 (2): 383–396. doi:10.1016/j.cell.2014.04.052. PMC   4149873 . PMID   25018103.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ↑ Chavali M, Ulloa-Navas MJ, Pérez-Borredá P, Garcia-Verdugo JM, McQuillen PS, Huang EJ; et al. (2020). "Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury" (PDF). Neuron. 108 (6): 1130–1145.e5. doi:10.1016/j.neuron.2020.09.033. PMC   7769920 . PMID   33086038.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ↑ Norris, Jeffrey (11 February 2011). "Pace Picks Up for Clinical Trials to Evaluate Stem Cell Therapies". UCSF. Retrieved 2021-09-30.
  19. ↑ Weiler, Nicholas (3 October 2019). "Stem cell studies offer hope for childhood neurological condition". ScienceDaily. Retrieved 2021-09-30.
  20. ↑ "Professor David Rowitch FMedSci". The Academy of Medical Sciences. Retrieved 2021-09-30.
  21. ↑ "Royal Society elects outstanding new Fellows and Foreign Members". The Royal Society. 6 May 2021. Retrieved 2021-09-30.
  22. ↑ "National Advisory Child Health and Human Development Council Roster". NICHD. Retrieved 2021-09-30.
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