Richard Carthew

Last updated
Richard W. Carthew
Born (1956-09-05) 5 September 1956 (age 67)
Toronto, Ontario, Canada
Alma mater Massachusetts Institute of Technology
Scientific career
FieldsBiology
Institutions Northwestern University
Thesis Characterization of human Class II transcription factors  (1987)
Doctoral advisor Phillip A. Sharp
Website sites.northwestern.edu/carthewlab/

Richard William Carthew (born 5 September 1956) is a developmental biologist and quantitative biologist at Northwestern University. He is a professor of molecular biosciences and is the director of the NSF-Simons Center for Quantitative Biology.

Contents

Education and early career

Carthew received his B.Sc. degree in biology at Queen's University in 1978. There, he pursued his interests in ecology by performing research under the supervision of Ted Brown [1] on the environmental adaptation of cyanobacteria. Carthew continued his studies at University of Toronto, where he received a M.Sc. degree in botany with Johann Hellebust. At the same time, he pursued training in music composition at the Royal Conservatory of Music in Toronto.

Upon completion of his degree, Carthew worked for two years as a research technician under the supervision of Jack Greenblatt at the Banting and Best Department of Medical Research in Toronto. In this time, Carthew studied the biochemistry of eukaryotic gene transcription and decided to forgo a career in music for one in the biomedical sciences. In 1982, Carthew began his PhD studies at the Massachusetts Institute of Technology where he performed his thesis research in the lab of Phillip A. Sharp. During his doctoral career, Carthew transformed the Electrophoresis Mobility Shift Assay or EMSA into an assay that could detect sequence-specific DNA-binding proteins from crude cell extracts. [2] Using this method, he identified and studied the HeLa cell transcription factor USF and its role in regulating gene transcription. [3] [4] Carthew also played a role in popularizing the now-common use in the biomedical literature of having multiple authors of a paper as "co-first authors". Carthew and fellow graduate student Lewis Chodosh decided to adopt this mechanism for their joint publication [2] in Cell, inspired by its use by Andrew Fire and Mark Samuels. [5] This novel feature of their paper was noticed by many, and subsequently adopted in other papers.

Following his graduate work, Carthew pursued post-doctoral research at the University of California Berkeley as a Helen Hay Whitney fellow. Carthew worked under the direction of Gerald M. Rubin on the molecular mechanisms of compound eye development in Drosophila melanogaster . He showed that the RING finger domain protein Seven in Absentia is essential for multipotent eye cells to adopt an R7 photoreceptor cell fate. [6] In subsequent work, he showed that Seven in Absentia is activated by the Ras signal transduction pathway and acts as an E3 ubiquitin ligase to rapidly degrade a transcriptional repressor of R7 cell differentiation. [7] [8]

Faculty career

Carthew started his independent research group in 1992 at the University of Pittsburgh in the Department of Biological Sciences. He became a tenured associate professor in 1998 and full professor in 2001. In 2001, Carthew moved to Northwestern University and became a full professor in the Department of Molecular Biosciences, which is located on the Evanston campus. He was appointed the Owen L. Coon Professor of Molecular Biology in 2006. Carthew served as leader of the Chromatin and Nuclear Dynamics Program in Northwestern’s Robert H. Lurie Comprehensive Cancer Center from 2012 to 2018. He served as director of the NCI funded Oncogenesis and Developmental Biology Training Program from 2007-2014. He currently serves as director of the NIGMS funded Training Program in Cellular and Molecular Basis of Disease at Northwestern.

In the early phase of Carthew lab research, a number of firsts were achieved. The Carthew group was the first to establish the Drosophila eye as a model system to study planar cell polarity. [9] It was the first group to use Drosophila as a disease model to screen and test small molecule drugs for potential efficacy in disease treatment. [10] It was the first group to provide genetic evidence that Frizzled proteins were Wnt receptors in vivo. [11] [12] In 1998, the group discovered that Drosophila were capable of RNAi or RNA interference. [12] The labs of Andrew Fire and Craig Mello had just demonstrated a key role for double-stranded RNA as the trigger for RNAi in the nematode Caenorhabditis elegans, [13] a discovery culminating in a Nobel Prize for Fire and Mello in 2006. By showing that RNAi also existed in another animal species, the Carthew group stimulated the search for RNAi in mammals, as well as the adoption of Drosophila as a premier model to study the biochemical and genetic mechanisms of RNAi. The Carthew group also developed the first and second generations of transgene systems for performing RNAi against any Drosophila gene at any stage of the life cycle in a tissue- or cell-specific manner. [14] [15] The second generation system was later expanded into a genome-wide collection of transgenic lines targeting all annotated genes. [16] The Carthew lab has continued pursuing the mechanisms and functions of the small non-coding RNA world that was first glimpsed through the lens of RNAi. The group has been addressing how and why small interfering RNAs (siRNAs) and microRNAs (miRNAs) regulate gene expression.

Since 2004, the Carthew group has also pursued questions related to quantitative issues of development. Inspired by the mathematical biologist D'Arcy Thompson and his seminal book On Growth and Form, the group showed that the topology of epithelial cells in the Drosophila eye is constrained due to a tendency for the cells to minimize surface energy. [17] This pioneering work emerged at the same time as other groups around the world also began addressing physical aspects of morphogenesis. Recent work in the Carthew lab has turned to dynamical features of gene expression as cells undergo lineage restriction during development. [18] This work has focused on the importance of time as a dimension in animal development and how gene regulatory networks are designed to provide temporal flexibility to development. The Carthew group found that when developmental tempo is slowed down by limiting cell metabolism, gene repressors become redundant during lineage restriction, and the entire microRNA family is rendered non-essential for development in general. [19]

NSF-Simons Center for Quantitative Biology

In July 2018, Carthew became Director of the newly founded NSF-Simons Center for Quantitative Biology at Northwestern University. Co-funded by a public-private partnership between the National Science Foundation and Simons Foundation, the Center for Quantitative Biology contains 12 Northwestern faculty members who are experts in developmental biology, applied mathematics, and pure mathematics. The Center's mission is to greatly expand the application of mathematics to study of important questions in developmental biology. This is done by supporting interdisciplinary research within the Center and stimulating interdisciplinary research and training activities across the United States. These efforts are augmented by the efforts of three other NSF-Simons Centers located across the country.

Selected publications

Related Research Articles

<span class="mw-page-title-main">Homeobox</span> DNA pattern affecting anatomy development

A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. Mutations in a homeobox may change large-scale anatomical features of the full-grown organism.

The RNA-induced silencing complex, or RISC, is a multiprotein complex, specifically a ribonucleoprotein, which functions in gene silencing via a variety of pathways at the transcriptional and translational levels. Using single-stranded RNA (ssRNA) fragments, such as microRNA (miRNA), or double-stranded small interfering RNA (siRNA), the complex functions as a key tool in gene regulation. The single strand of RNA acts as a template for RISC to recognize complementary messenger RNA (mRNA) transcript. Once found, one of the proteins in RISC, Argonaute, activates and cleaves the mRNA. This process is called RNA interference (RNAi) and it is found in many eukaryotes; it is a key process in defense against viral infections, as it is triggered by the presence of double-stranded RNA (dsRNA).

<span class="mw-page-title-main">Robert G. Roeder</span> American biochemist

Robert G. Roeder is an American biochemist. He is known as a pioneer scientist in eukaryotic transcription. He discovered three distinct nuclear RNA polymerases in 1969 and characterized many proteins involved in the regulation of transcription, including basic transcription factors and the first mammalian gene-specific activator over five decades of research. He is the recipient of the Gairdner Foundation International Award in 2000, the Albert Lasker Award for Basic Medical Research in 2003, and the Kyoto Prize in 2021. He currently serves as Arnold and Mabel Beckman Professor and Head of the Laboratory of Biochemical and Molecular Biology at The Rockefeller University.

Gene structure is the organisation of specialised sequence elements within a gene. Genes contain most of the information necessary for living cells to survive and reproduce. In most organisms, genes are made of DNA, where the particular DNA sequence determines the function of the gene. A gene is transcribed (copied) from DNA into RNA, which can either be non-coding (ncRNA) with a direct function, or an intermediate messenger (mRNA) that is then translated into protein. Each of these steps is controlled by specific sequence elements, or regions, within the gene. Every gene, therefore, requires multiple sequence elements to be functional. This includes the sequence that actually encodes the functional protein or ncRNA, as well as multiple regulatory sequence regions. These regions may be as short as a few base pairs, up to many thousands of base pairs long.

<span class="mw-page-title-main">Ultrabithorax</span> Protein-coding gene found in Drosophila melanogaster

Ultrabithorax (Ubx) is a homeobox gene found in insects, and is used in the regulation of patterning in morphogenesis. There are many possible products of this gene, which function as transcription factors. Ubx is used in the specification of serially homologous structures, and is used at many levels of developmental hierarchies. In Drosophila melanogaster it is expressed in the third thoracic (T3) and first abdominal (A1) segments and represses wing formation. The Ubx gene regulates the decisions regarding the number of wings and legs the adult flies will have. The developmental role of the Ubx gene is determined by the splicing of its product, which takes place after translation of the gene. The specific splice factors of a particular cell allow the specific regulation of the developmental fate of that cell, by making different splice variants of transcription factors. In D. melanogaster, at least six different isoforms of Ubx exist.

<i>Krüppel</i>

Krüppel is a gap gene in Drosophila melanogaster, located on the 2R chromosome, which encodes a zinc finger C2H2 transcription factor. Gap genes work together to establish the anterior-posterior segment patterning of the insect through regulation of the transcription factor encoding pair rule genes. These genes in turn regulate segment polarity genes. Krüppel means "cripple" in German, named for the crippled appearance of mutant larvae, who have failed to develop proper thoracic and anterior segments in the abdominal region. Mutants can also have abdominal mirror duplications.

Douglas A. Melton is an American medical researcher who is the Xander University Professor at Harvard University, and was an investigator at the Howard Hughes Medical Institute until 2022. Melton serves as the co-director of the Harvard Stem Cell Institute and was the first co-chairman of the Harvard University Department of Stem Cell and Regenerative Biology. Melton is the founder of several biotech companies including Gilead Sciences, Ontogeny, iPierian, and Semma Therapeutics. Melton holds membership in the National Academy of the Sciences, the American Academy of Arts and Sciences, and is a founding member of the International Society for Stem Cell Research.

mir-7 microRNA precursor

This family represents the microRNA (miRNA) precursor mir-7. This miRNA has been predicted or experimentally confirmed in a wide range of species. miRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product. In this case the mature sequence comes from the 5' arm of the precursor. The extents of the hairpin precursors are not generally known and are estimated based on hairpin prediction. The involvement of Dicer in miRNA processing suggests a relationship with the phenomenon of RNA interference.

<span class="mw-page-title-main">Pair-rule gene</span> Gene involved in the development of segmented embryos of insects

A pair-rule gene is a type of gene involved in the development of the segmented embryos of insects. Pair-rule genes are expressed as a result of differing concentrations of gap gene proteins, which encode transcription factors controlling pair-rule gene expression. Pair-rule genes are defined by the effect of a mutation in that gene, which causes the loss of the normal developmental pattern in alternating segments.

<span class="mw-page-title-main">PBX1</span> Protein found in humans

Pre-B-cell leukemia transcription factor 1 is a protein that in humans is encoded by the PBX1 gene. The homologous protein in Drosophila is known as extradenticle, and causes changes in embryonic development.

<span class="mw-page-title-main">Planar cell polarity</span>

Planar cell polarity (PCP) is the protein-mediated signaling that coordinates the orientation of cells in a layer of epithelial tissue. In vertebrates, examples of mature PCP oriented tissue are the stereo-cilia bundles in the inner ear, motile cilia of the epithelium, and cell motility in epidermal wound healing. Additionally, PCP is known to be crucial to major developmental time points including coordinating convergent extension during gastrulation and coordinating cell behavior for neural tube closure. Cells orient themselves and their neighbors by establishing asymmetric expression of PCP components on opposing cell members within cells to establish and maintain the directionality of the cells. Some of these PCP components are transmembrane proteins which can proliferate the orientation signal to the surrounding cells.

<span class="mw-page-title-main">Notch proteins</span> Protein family

Notch proteins are a family of type 1 transmembrane proteins that form a core component of the Notch signaling pathway, which is highly conserved in animals. The Notch extracellular domain mediates interactions with DSL family ligands, allowing it to participate in juxtacrine signaling. The Notch intracellular domain acts as a transcriptional activator when in complex with CSL family transcription factors. Members of this type 1 transmembrane protein family share several core structures, including an extracellular domain consisting of multiple epidermal growth factor (EGF)-like repeats and an intracellular domain transcriptional activation domain (TAD). Notch family members operate in a variety of different tissues and play a role in a variety of developmental processes by controlling cell fate decisions. Much of what is known about Notch function comes from studies done in Caenorhabditis elegans (C.elegans) and Drosophila melanogaster. Human homologs have also been identified, but details of Notch function and interactions with its ligands are not well known in this context.

Maternal to zygotic transition (MZT), also known as embryonic genome activation, is the stage in embryonic development during which development comes under the exclusive control of the zygotic genome rather than the maternal (egg) genome. The egg contains stored maternal genetic material mRNA which controls embryo development until the onset of MZT. After MZT the diploid embryo takes over genetic control. This requires both zygotic genome activation (ZGA), and degradation of maternal products. This process is important because it is the first time that the new embryonic genome is utilized and the paternal and maternal genomes are used in combination. The zygotic genome now drives embryo development.

<span class="mw-page-title-main">RNA interference</span> Biological process of gene regulation

RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by other names, including co-suppression, post-transcriptional gene silencing (PTGS), and quelling. The detailed study of each of these seemingly different processes elucidated that the identity of these phenomena were all actually RNAi. Andrew Fire and Craig C. Mello shared the 2006 Nobel Prize in Physiology or Medicine for their work on RNAi in the nematode worm Caenorhabditis elegans, which they published in 1998. Since the discovery of RNAi and its regulatory potentials, it has become evident that RNAi has immense potential in suppression of desired genes. RNAi is now known as precise, efficient, stable and better than antisense therapy for gene suppression. Antisense RNA produced intracellularly by an expression vector may be developed and find utility as novel therapeutic agents.

mir-279 is a short RNA molecule found in Drosophila melanogaster that belongs to a class of molecules known as microRNAs. microRNAs are ~22nt-long non-coding RNAs that post-transcriptionally regulate the expression of genes, often by binding to the 3' untranslated region of mRNA, targeting the transcript for degradation. miR-279 has diverse tissue-specific functions in the fly, influencing developmental processes related to neurogenesis and oogenesis, as well as behavioral processes related to circadian rhythms. The varied roles of mir-279, both in the developing and adult fly, highlight the utility of microRNAs in regulating unique biological processes.

<span class="mw-page-title-main">Michael Rosbash</span> American geneticist and chronobiologist (born 1944)

Michael Morris Rosbash is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University and investigator at the Howard Hughes Medical Institute. Rosbash's research group cloned the Drosophila period gene in 1984 and proposed the Transcription Translation Negative Feedback Loop for circadian clocks in 1990. In 1998, they discovered the cycle gene, clock gene, and cryptochrome photoreceptor in Drosophila through the use of forward genetics, by first identifying the phenotype of a mutant and then determining the genetics behind the mutation. Rosbash was elected to the National Academy of Sciences in 2003. Along with Michael W. Young and Jeffrey C. Hall, he was awarded the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm".

<i>Homeotic protein bicoid</i> Protein-coding gene in the species Drosophila melanogaster

Homeotic protein bicoid is encoded by the bcd maternal effect gene in Drosophilia. Homeotic protein bicoid concentration gradient patterns the anterior-posterior (A-P) axis during Drosophila embryogenesis. Bicoid was the first protein demonstrated to act as a morphogen. Although bicoid is important for the development of Drosophila and other higher dipterans, it is absent from most other insects, where its role is accomplished by other genes.

<span class="mw-page-title-main">Robin Allshire</span> British academic

Robin Campbell Allshire is Professor of Chromosome Biology at University of Edinburgh and a Wellcome Trust Principal Research Fellow. His research group at the Wellcome Trust Centre for Cell Biology focuses on the epigenetic mechanisms governing the assembly of specialised domains of chromatin and their transmission through cell division.

Elizabeth Gavis is an American biologist who is the Damon B. Pfeiffer Professor of Life Sciences, at Princeton University. Gavis served as the President of the North American Drosophila Board of Directors in 2011.

<span class="mw-page-title-main">Hunchback (gene)</span> Maternal effect gene and gap gene

Hunchback is a maternal effect and zygotic gene expressed in the embryos of the fruit fly Drosophila melanogaster. In maternal effect genes, the RNA or protein from the mother’s gene is deposited into the oocyte or embryo before the embryo can express its own zygotic genes.

References

  1. ↑ Smol, John P. (December 1986). "A biographical sketch of Seward R. (Ted) Brown". Hydrobiologia. 143 (1): 9–11. doi:10.1007/BF00026638. ISSN   0018-8158. S2CID   36992974.
  2. 1 2 Carthew, Richard W.; Chodosh, Lewis A.; Sharp, Phillip A. (December 1985). "An RNA polymerase II transcription factor binds to an upstream element in the adenovirus major late promoter". Cell. 43 (2): 439–448. doi: 10.1016/0092-8674(85)90174-6 . ISSN   0092-8674. PMID   4075400.
  3. ↑ Chodosh, L A; Carthew, R W; Sharp, P A (December 1986). "A single polypeptide possesses the binding and transcription activities of the adenovirus major late transcription factor". Molecular and Cellular Biology. 6 (12): 4723–4733. doi: 10.1128/mcb.6.12.4723 . ISSN   0270-7306. PMC   367258 . PMID   3796614.
  4. ↑ Carthew, R W; Chodosh, L A; Sharp, P A (1987-11-01). "The major late transcription factor binds to and activates the mouse metallothionein I promoter". Genes & Development. 1 (9): 973–980. doi: 10.1101/gad.1.9.973 . ISSN   0890-9369. PMID   3428603.
  5. ↑ Samuels, Mark; Fire, Andrew (1982). "Separation and characterization of factors mediating accurate transcription by RNA polymerase II". Journal of Biological Chemistry. 257 (23): 14419–14427. doi: 10.1016/S0021-9258(19)45397-0 . PMID   7142220.
  6. ↑ Carthew, Richard W.; Rubin, Gerald M. (November 1990). "seven in absentia, a gene required for specification of R7 cell fate in the Drosophila eye". Cell. 63 (3): 561–577. doi:10.1016/0092-8674(90)90452-k. ISSN   0092-8674. PMID   2146028. S2CID   1049619.
  7. ↑ Kauffmann, R C; Li, S; Gallagher, P A; Zhang, J; Carthew, R W (1996-09-01). "Ras1 signaling and transcriptional competence in the R7 cell of Drosophila". Genes & Development. 10 (17): 2167–2178. doi: 10.1101/gad.10.17.2167 . ISSN   0890-9369. PMID   8804311.
  8. ↑ Li, Songhui; Li, Ying; Carthew, Richard W; Lai, Zhi-Chun (August 1997). "Photoreceptor Cell Differentiation Requires Regulated Proteolysis of the Transcriptional Repressor Tramtrack". Cell. 90 (3): 469–478. doi: 10.1016/s0092-8674(00)80507-3 . ISSN   0092-8674. PMID   9267027. S2CID   7853369.
  9. ↑ Zheng, L; Zhang, J.; Carthew, R.W. (1995). "frizzled regulates mirror-symmetric pattern formation in the Drosophila eye". Development. 121 (9): 3045–3055. doi:10.1242/dev.121.9.3045. PMID   7555730.
  10. ↑ Kauffmann, R. C.; Qian, Y.; Vogt, A.; Sebti, S. M.; Hamilton, A. D.; Carthew, R. W. (1995-11-21). "Activated Drosophila Ras1 is selectively suppressed by isoprenyl transferase inhibitors". Proceedings of the National Academy of Sciences. 92 (24): 10919–10923. Bibcode:1995PNAS...9210919K. doi: 10.1073/pnas.92.24.10919 . ISSN   0027-8424. PMC   40542 . PMID   7479910.
  11. ↑ Zhang, J.; Carthew, R. W. (1998-08-15). "Interactions between Wingless and DFz2 during Drosophila wing development". Development. 125 (16): 3075–3085. doi:10.1242/dev.125.16.3075. ISSN   0950-1991. PMID   9671581.
  12. 1 2 Kennerdell, Jason R; Carthew, Richard W (December 1998). "Use of dsRNA-Mediated Genetic Interference to Demonstrate that frizzled and frizzled 2 Act in the Wingless Pathway". Cell. 95 (7): 1017–1026. doi: 10.1016/s0092-8674(00)81725-0 . ISSN   0092-8674. PMID   9875855. S2CID   18443540.
  13. ↑ Fire, Andrew; Xu, SiQun; Montgomery, Mary K.; Kostas, Steven A.; Driver, Samuel E.; Mello, Craig C. (February 1998). "Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans". Nature. 391 (6669): 806–811. Bibcode:1998Natur.391..806F. doi:10.1038/35888. ISSN   1476-4687. PMID   9486653. S2CID   4355692.
  14. ↑ Kennerdell, Jason R.; Carthew, Richard W. (August 2000). "Heritable gene silencing in Drosophila using double-stranded RNA". Nature Biotechnology. 18 (8): 896–898. doi:10.1038/78531. ISSN   1087-0156. PMID   10932163. S2CID   22987734.
  15. ↑ Sik Lee, Young; Carthew, Richard W. (2003-08-01). "Making a better RNAi vector for Drosophila: use of intron spacers". Methods. RNA interference. 30 (4): 322–329. doi:10.1016/S1046-2023(03)00051-3. ISSN   1046-2023. PMID   12828946.
  16. ↑ Dietzl, Georg; Chen, Doris; Schnorrer, Frank; Su, Kuan-Chung; Barinova, Yulia; Fellner, Michaela; Gasser, Beate; Kinsey, Kaolin; Oppel, Silvia; Scheiblauer, Susanne; Couto, Africa (July 2007). "A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila". Nature. 448 (7150): 151–156. Bibcode:2007Natur.448..151D. doi:10.1038/nature05954. ISSN   1476-4687. PMID   17625558. S2CID   4392409.
  17. ↑ Hayashi, Takashi; Carthew, Richard W. (October 2004). "Surface mechanics mediate pattern formation in the developing retina". Nature. 431 (7009): 647–652. Bibcode:2004Natur.431..647H. doi:10.1038/nature02952. ISSN   0028-0836. PMID   15470418. S2CID   4340509.
  18. ↑ Peláez, Nicolás; Gavalda-Miralles, Arnau; Wang, Bao; Navarro, Heliodoro Tejedor; Gudjonson, Herman; Rebay, Ilaria; Dinner, Aaron R; Katsaggelos, Aggelos K; Amaral, Luís AN; Carthew, Richard W (2015). "Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation". eLife. 4. doi: 10.7554/eLife.08924 . ISSN   2050-084X. PMC   4720516 . PMID   26583752.
  19. ↑ Cassidy, Justin J. Bernasek, Sebastian M. Bakker, Rachael Giri, Ritika Peláez, Nicolás Eder, Bryan Bobrowska, Anna Bagheri, Neda Nunes Amaral, Luis A. Carthew, Richard W. (2019-07-25). "Repressive gene regulation synchronizes development with cellular metabolism". Cell. 178 (4). Elsevier: 980–992.e17. doi:10.1016/j.cell.2019.06.023. OCLC   1111530678. PMC   6865806 . PMID   31353220.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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