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Gary Struhl is an American research scientist whose primary areas of research are developmental biology and genetics and genomics. He works as a professor at Columbia University Medical Center, teaching neuroscience within the Department of Genetics and Development. [1]
Gary Struhl has a brother, Kevin Struhl, who was also recognized as a member of the National Academy of Sciences. Both Gary and Kevin studied at MIT for their undergraduate degrees, but Gary attended Cambridge for his doctorate degree while Kevin completed his studies at Stanford University. Both did postdoctoral research at Cambridge, but their research differs, as Kevin works on eukaryotic gene regulation. [2]
Struhl obtained his undergraduate degree from the Massachusetts Institute of Technology. [3] He received his doctorate from the University of Cambridge in the United Kingdom, and then he completed his postdoctoral fellowships both at the University of Cambridge and at Harvard University. He serves as a professor at Columbia University Medical Center in the Department of Genetics and Development, in neuroscience. [1] He is married to Iva Greenwald, with whom he has a daughter.
Struhl has his own lab at Columbia University, the Struhl Lab at Columbia’s Mortimer B Zuckerman Mind Brain Behavior Institute.[ citation needed ] A large portion of Struhl’s research centers around the common fruit fly, or Drosophila, and the developmental genetics surrounding this type of insect. He was accepted into the American Academy of Arts and Sciences in 2005 and into the National Academy of Sciences for cellular and developmental biology in 2008. [4]
In 1999, Struhl published a paper looking at the frizzled and frizzed2 proteins of Drosophila. For this paper, the amber mutation of fz2 was isolated to look at its effects on signal transduction. It was concluded that fz2 is a primary receptor of Wg in Drosophila and that without f2 or fz2, signal transduction was not able to occur. [5] Struhl also published a paper relating to frizzled function that analyzed the planar cell polarity of epithelial cells. In this paper, it was concluded that each of the cells has a mechanism that allows it to estimate the amount of asymmetric bridges, occurring between Stan and Stan plus Fz, that act as the link with neighboring cells. [6] This mechanism was thought to be the method of reading the local slope of tissue-wide gradients of Fz activity, and that through this, all of the cells come to point in one direction. [6]
Further research by Struhl and his associates was done into the control of Drosophila wing growth and its unified mechanism. [7] This paper concluded that Decapentaplegic (Dpp, a BMP) and Wingless (Wg, a Wnt) act together through a common mechanism in order to control wing growth as a function of morphogen range.
Struhl’s work with Epsin can be seen in a two decade span of several papers. His first major paper regarding Epsin was written in 2004, titled “Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch”. This paper proposed that Epsin was essential for cell signaling because it “targets mono-ubiquitinated DSL proteins to an endocytic recycling compartment that they must enter to be converted into active ligands”. [8] Additionally, he proposed that Epsin “may be required to target mono-ubiquitinated DSL proteins to a particular subclass of coated pits that have special properties essential for Notch activation”. [8] These two parts of the hypotheses were further tested and developed in some of Struhl’s more recent work and publications. He co-authored a paper that discussed Notch Activation by ligand endocytosis, and looked at the force exerted by the ligand on the notch. [9] In this paper, he stated that there were two models, the recycling models and the pulling models, that could help explain the requirement that the ligand must be endocytosed by Epsin in signal-sending cells. [9]
Another of Struhl’s papers investigated the requirement of the ligands to be endocytosed so that the Notch in signal-receiving cells could be activated. [10] The experiments and research of this paper supported and further extended their hypothesis from an earlier paper, showing that the mono-ubiquitination of the DSL proteins was essential for gaining access to the pathway that allows them to activate Notch.
Struhl co-authored a paper in which he discussed the three roles for notch in Drosophila R7 photoreceptor specification. In this paper, he wrote that the three distinct roles were to block photoreceptor differentiation, to enable the R7 cell to receive R8’s RTK signal to override the block from the first role, and to specify that the cell is an R7 and not an R1/6. [11]
A research article published by Struhl in the American Academy of Arts and Sciences journal looked at the relationship between epigenetic states and inheritance of cis-acting chromatin modifications. The key nucleosome in question was the H3K27me nucleosome. The paper concluded that H3K27me was a determinant of epigenetic memory, and that PRE-associated PRC2 propagates the mark as a requirement for perpetuating the memory. [12] In further research looking into the controls of Drosophila wing size, Struhl explored the mechanisms that limit growth as a function of time. Two constraints were identified that prevent the wing from further growth once it meets its intended size goal at the end of larval growth. These two factors were an intrinsic limit on the spread of morphogen and the capacity of ecdysone, a steroid hormone, to gate the ability of these wing cells to grow as a response to morphogen. [13]
Struhl along with research associates looked at the activation thresholds of C. elegans Notch proteins LIN-12 and GLP-1. [14] This article discussed the fact that Epsin is not required for Notch signaling in the species C. elegans, which means that greater force is now necessary to expose the cleavage site, and that the NRRs of these proteins are tuned to a lower force threshold.
In 2004, Struhl was involved in a controversy regarding research on Wnt signaling, which is a major pathway in human cancer and embryonic development. A postdoc named Siu-Kwong Chan performed experiments that came to the conclusion that the beta-catenin or Armadillo could transduce Wnt signals without entering the nucleus. Struhl attempted to replicate this experiment, but received opposite results for important aspects of the experiment. When he reached out to Chan, Chan admitted that large portions of the data had either been fabricated or was not performed. Because of this, Struhl had the paper retracted and Chan lost his position at Albert Einstein College of Medicine. Many came to Struhl’s defense, arguing that he was put in a very challenging position, but had no knowledge of this fraud, and that it was an unfortunate lesson for him to learn. [15]
In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.
The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.
A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.
In biology, cell signaling is the process by which a cell interacts with itself, other cells and the environment. Cell signaling is a fundamental property of all cellular life in prokaryotes and eukaryotes.
Compartments can be simply defined as separate, different, adjacent cell populations, which upon juxtaposition, create a lineage boundary. This boundary prevents cell movement from cells from different lineages across this barrier, restricting them to their compartment. Subdivisions are established by morphogen gradients and maintained by local cell-cell interactions, providing functional units with domains of different regulatory genes, which give rise to distinct fates. Compartment boundaries are found across species. In the hindbrain of vertebrate embryos, rhombomeres are compartments of common lineage outlined by expression of Hox genes. In invertebrates, the wing imaginal disc of Drosophila provides an excellent model for the study of compartments. Although other tissues, such as the abdomen, and even other imaginal discs are compartmentalized, much of our understanding of key concepts and molecular mechanisms involved in compartment boundaries has been derived from experimentation in the wing disc of the fruit fly.
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include cancer.
Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecular target of the natural teratogen cyclopamine. It also is the target of vismodegib, the first hedgehog pathway inhibitor to be approved by the U.S. Food and Drug Administration (FDA).
Epsins are a family of highly conserved membrane proteins that are important in creating membrane curvature. Epsins contribute to membrane deformations like endocytosis, and block vesicle formation during mitosis.
Decapentaplegic (Dpp) is a key morphogen involved in the development of the fruit fly Drosophila melanogaster and is the first validated secreted morphogen. It is known to be necessary for the correct patterning and development of the early Drosophila embryo and the fifteen imaginal discs, which are tissues that will become limbs and other organs and structures in the adult fly. It has also been suggested that Dpp plays a role in regulating the growth and size of tissues. Flies with mutations in decapentaplegic fail to form these structures correctly, hence the name. Dpp is the Drosophila homolog of the vertebrate bone morphogenetic proteins (BMPs), which are members of the TGF-β superfamily, a class of proteins that are often associated with their own specific signaling pathway. Studies of Dpp in Drosophila have led to greater understanding of the function and importance of their homologs in vertebrates like humans.
Peter Anthony Lawrence is a British developmental biologist at the Laboratory of Molecular Biology and the Zoology Department of the University of Cambridge. He was a staff scientist of the Medical Research Council from 1969 to 2006.
Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.
Protein numb homolog is a protein that in humans is encoded by the NUMB gene. The protein encoded by this gene plays a role in the determination of cell fates during development. The encoded protein, whose degradation is induced in a proteasome-dependent manner by MDM2, is a membrane-bound protein that has been shown to associate with EPS15, LNX1, and NOTCH1. Four transcript variants encoding different isoforms have been found for this gene.
Frizzled-6(Fz-6) is a protein that in humans is encoded by the FZD6 gene.
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.
Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice and humans. Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the SPATS1 protein when regulating the Wnt Signalling pathway.
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 metazoans. 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.
Proneural genes encode transcription factors of the basic helix-loop-helix (bHLH) class which are responsible for the development of neuroectodermal progenitor cells. Proneural genes have multiple functions in neural development. They integrate positional information and contribute to the specification of progenitor-cell identity. From the same ectodermal cell types, neural or epidermal cells can develop based on interactions between proneural and neurogenic genes. Neurogenic genes are so called because loss of function mutants show an increase number of developed neural precursors. On the other hand, proneural genes mutants fail to develop neural precursor cells.
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.
Richard William Carthew 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.
Iva Susan Greenwald is an American biologist who is Professor of Cell and Molecular Biology at Columbia University. She studies cell-cell interactions and cell fate specification in C. elegans. She is particularly interested in LIN-12/Notch proteins, which is the receptor of one of the major signalling systems that determines the fate of cells.
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