Michael Levine is an American developmental and cell biologist at Princeton University , where he is the Director of the Lewis-Sigler Institute for Integrative Genomics and a Professor of Molecular Biology.
41-500: The ParaHox gene cluster is an array of homeobox genes (involved in morphogenesis , the regulation of patterns of anatomical development) from the Gsx , Xlox ( Pdx ) and Cdx gene families. These genes were first shown to be arranged into a physically-linked chromosomal cluster in amphioxus , an invertebrate with a single member of each of the three gene families. All the ParaHox genes in
82-407: A 60- amino acid long domain composed of three alpha helixes. The following shows the consensus homeodomain (~60 amino acid chain): Helix 2 and helix 3 form a so-called helix-turn-helix (HTH) structure, where the two alpha helices are connected by a short loop region. The N-terminal two helices of the homeodomain are antiparallel and the longer C-terminal helix is roughly perpendicular to
123-518: A Ph.D. in molecular biophysics and biochemistry . Levine joined the Princeton faculty in 2015, and had been a professor at UC Berkeley after leaving UCSD in 1996. Levine was a post-doc with Walter Gehring in Switzerland from 1982 to 1983. There, he co-discovered the homeobox with Ernst Hafen and fellow post-doc William McGinnis : After learning that Ultrabithorax , a gene that specifies
164-468: A common eukaryotic ancestry for TALE and non-TALE homeodomain proteins. The Hox genes in humans are organized in four chromosomal clusters: ParaHox genes are analogously found in four areas. They include CDX1 , CDX2 , CDX4 ; GSX1 , GSX2 ; and PDX1 . Other genes considered Hox-like include EVX1 , EVX2 ; GBX1 , GBX2 ; MEOX1 , MEOX2 ; and MNX1 . The NK-like (NKL) genes, some of which are considered "MetaHox", are grouped with Hox-like genes into
205-442: A gene called antennapedia that caused this homeotic phenotype. Analysis of antennapedia revealed that this gene contained a 180 base pair sequence that encoded a DNA binding domain, which William McGinnis termed the "homeobox". The existence of additional Drosophila genes containing the antennapedia homeobox sequence was independently reported by Ernst Hafen, Michael Levine , William McGinnis , and Walter Jakob Gehring of
246-428: A homeobox and a paired domain that also binds DNA to increase binding specificity, though some Pax genes have lost all or part of the homeobox sequence. Pax genes function in embryo segmentation , nervous system development, generation of the frontal eye fields , skeletal development, and formation of face structures. Pax 6 is a master regulator of eye development, such that the gene is necessary for development of
287-644: A large ANTP-like group. Humans have a "distal-less homeobox" family : DLX1 , DLX2 , DLX3 , DLX4 , DLX5 , and DLX6 . Dlx genes are involved in the development of the nervous system and of limbs. They are considered a subset of the NK-like genes. Human TALE (Three Amino acid Loop Extension) homeobox genes for an "atypical" homeodomain consist of 63 rather than 60 amino acids: IRX1 , IRX2 , IRX3 , IRX4 , IRX5 , IRX6 ; MEIS1 , MEIS2 , MEIS3 ; MKX ; PBX1 , PBX2 , PBX3 , PBX4 ; PKNOX1 , PKNOX2 ; TGIF1 , TGIF2 , TGIF2LX , TGIF2LY . In addition, humans have
328-418: A postdoctoral fellow with Gerry Rubin . He then joined the faculty of Columbia University , where he "led the discovery of the modular organization of the regulatory regions of developmental genes." After isolating the even-skipped ( eve ) gene, Levine's team determined that each of the seven stripes was produced by separate enhancers. With further study they discovered that both a set of activators and
369-445: A set of repressors worked together to shape the expression of eve in the second stripe, and determined that the repressors shut down only their binding enhancers, leaving other enhancers free of repression. Joseph Corbo said of the work, "Before Levine's studies of even-skipped stripe 2, it wasn't clear how you generated spatially restricted patterns of gene expression from initially broad crude gradients of morphogens. I think that
410-451: A single homeodomain protein is usually not enough to recognize specific target gene promoters, making cofactor binding an important mechanism for controlling binding sequence specificity and target gene expression. To achieve higher target specificity, homeodomain proteins form complexes with other transcription factors to recognize the promoter region of a specific target gene. Homeodomain proteins function as transcription factors due to
451-399: Is a term coined by William Bateson to describe the outright replacement of a discrete body part with another body part, e.g. antennapedia —replacement of the antenna on the head of a fruit fly with legs. The "homeo-" prefix in the words "homeobox" and "homeodomain" stems from this mutational phenotype , which is observed when some of these genes are mutated in animals . The homeobox domain
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#1733085542591492-413: Is accepted that the three major animal ANTP-class clusters, Hox, ParaHox, and NK (MetaHox), are the result of segmental duplications. A first duplication created MetaHox and ProtoHox, the latter of which later duplicated into Hox and ParaHox. The clusters themselves were created by tandem duplications of a single ANTP-class homeobox gene. Gene duplication followed by neofunctionalization is responsible for
533-411: Is also prominent in work with the sea squirt , Ciona intestinalis , an invertebrate that facilitates study of development. For example, this work included insights into classical myodeterminants and the composition of the notochord , the defining tissue of the chordate phylum . Levine cites as a significant influence his instructor Fred Wilt (taking his developmental biology class "was probably
574-465: Is called ectopia . For example, when one gene is lost the segment develops into a more anterior one, while a mutation that leads to a gain of function causes a segment to develop into a more posterior one. Famous examples are Antennapedia and bithorax in Drosophila , which can cause the development of legs instead of antennae and the development of a duplicated thorax, respectively. In vertebrates,
615-683: Is known to use the polycomb and trithorax complexes to maintain the expression of Hox genes after the down-regulation of the pair-rule and gap genes that occurs during larval development. Polycomb-group proteins can silence the Hox genes by modulation of chromatin structure. Mutations to homeobox genes can produce easily visible phenotypic changes in body segment identity, such as the Antennapedia and Bithorax mutant phenotypes in Drosophila . Duplication of homeobox genes can produce new body segments, and such duplications are likely to have been important in
656-448: The 2R genome duplications at the base of vertebrate evolution. Some vertebrates, notably chondrichthyan fish and coelacanths , have retained an additional ParaHox gene (PDX2). The ParaHox gene cluster has been proposed to be a paralogue, or evolutionary sister, of the Hox gene cluster; the two gene clusters being descendent from a segmental duplication early in animal evolution, preceding
697-679: The University of Basel in Switzerland and Matthew P. Scott and Amy Weiner of Indiana University in Bloomington in 1984. Isolation of homologous genes by Edward de Robertis and William McGinnis revealed that numerous genes from a variety of species contained the homeobox. Subsequent phylogenetic studies detailing the evolutionary relationship between homeobox-containing genes showed that these genes are present in all bilaterian animals. The characteristic homeodomain protein fold consists of
738-455: The evolution of segmented animals. Phylogenetic analysis of homeobox gene sequences and homeodomain protein structures suggests that the last common ancestor of plants, fungi, and animals had at least two homeobox genes. Molecular evidence shows that some limited number of Hox genes have existed in the Cnidaria since before the earliest true Bilatera , making these genes pre- Paleozoic . It
779-539: The DNA binding properties of the conserved HTH motif. Homeodomain proteins are considered to be master control genes, meaning that a single protein can regulate expression of many target genes. Homeodomain proteins direct the formation of the body axes and body structures during early embryonic development . Many homeodomain proteins induce cellular differentiation by initiating the cascades of coregulated genes required to produce individual tissues and organs . Other proteins in
820-468: The Gsx gene family which plays a role in brain (not foregut) development in vertebrates. Homeobox 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. Homeoboxes are found within genes that are involved in
861-469: The amphioxus genome are therefore in the ParaHox gene cluster. In contrast, the human genome has six ParaHox genes ( GSX1 , GSX2 , PDX1 , CDX1 , CDX2 , CDX4 ), of which three genes ( GSX1 , PDX1 (=IPF1), CDX2 ) are physically linked to form a human ParaHox gene cluster on chromosome 13 . Mouse has a homologous ParaHox gene cluster on chromosome 5. The other three human ParaHox genes are remnants from duplicated ParaHox gene clusters that were generated in
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#1733085542591902-585: The axes established by the first two. It is this third helix that interacts directly with DNA via a number of hydrogen bonds and hydrophobic interactions, as well as indirect interactions via water molecules, which occur between specific side chains and the exposed bases within the major groove of the DNA. Homeodomain proteins are found in eukaryotes . Through the HTH motif, they share limited sequence similarity and structural similarity to prokaryotic transcription factors, such as lambda phage proteins that alter
943-514: The beta-carbon with the main chain: for cro and repressor proteins the glycine appears to be mandatory, whereas for many of the homeotic and other DNA-binding proteins the requirement is relaxed. Homeodomains can bind both specifically and nonspecifically to B-DNA with the C-terminal recognition helix aligning in the DNA's major groove and the unstructured peptide "tail" at the N-terminus aligning in
984-416: The development of wings, showed a localized pattern of expression similar to that of Antennapedia , they decided to revisit the classic papers of Ed Lewis . In 1978, Lewis had proposed that all these homeotic genes (the ones that tell animals where to put a wing and where to put a leg and so on) arose from a common ancestral gene. So McGinnis carved up the Antennapedia gene and, using those pieces as probes,
1025-436: The divergence of cnidarians and bilaterian animals. It has been suggested that an ancient role of the ParaHox gene cluster in bilaterians was the specify or pattern the through-gut, with Gsx patterning the mouth, Xlox (=Pdx) patterning the midgut and Cdx marking the anus. Gene expression and functional data lends tentative support to this hypothesis, although in many animals the roles of the genes have changed in evolution, notably
1066-552: The even-skipped stripe 2 studies were the defining studies that showed how an organism can interpret those gradients and turn them into specific patterns of gene expression. To me that's Mike's crowning achievement." After earning tenure in only four years at Columbia, Levine moved to UCSD in 1991, where he added the sea squirt , Ciona intestinalis , to his repertoire. Although much of Levine's work, including his homeobox studies, has been done in Drosophila Levine's team
1107-417: The expression of genes in prokaryotes . The HTH motif shows some sequence similarity but a similar structure in a wide range of DNA-binding proteins (e.g., cro and repressor proteins , homeodomain proteins, etc.). One of the principal differences between HTH motifs in these different proteins arises from the stereochemical requirement for glycine in the turn which is needed to avoid steric interference of
1148-484: The family, such as NANOG are involved in maintaining pluripotency and preventing cell differentiation. Hox genes and their associated microRNAs are highly conserved developmental master regulators with tight tissue-specific, spatiotemporal control. These genes are known to be dysregulated in several cancers and are often controlled by DNA methylation. The regulation of Hox genes is highly complex and involves reciprocal interactions, mostly inhibitory. Drosophila
1189-826: The following homeobox genes and proteins: Michael Levine (biologist) Levine previously held appointments at the University of California, Berkeley , the University of California, San Diego , and Columbia University . He is notable for co-discovering the Homeobox in 1983 and for discovering the organization of the regulatory regions of developmental genes. Levine was born in West Hollywood and raised in Los Angeles . Levine studied biology as an undergraduate at UC Berkeley , studying biology with Allan Wilson and graduating in 1976. He went on to graduate studies at Yale , where he studied with Alan Garen and in 1981 received
1230-756: The four paralog clusters are partially redundant in function, but have also acquired several derived functions. For example, HoxA and HoxD specify segment identity along the limb axis. Specific members of the Hox family have been implicated in vascular remodeling, angiogenesis , and disease by orchestrating changes in matrix degradation, integrins, and components of the ECM. HoxA5 is implicated in atherosclerosis. HoxD3 and HoxB3 are proinvasive, angiogenic genes that upregulate b3 and a5 integrins and Efna1 in ECs, respectively. HoxA3 induces endothelial cell (EC) migration by upregulating MMP14 and uPAR. Conversely, HoxD10 and HoxA5 have
1271-500: The initial letters of the names of three proteins where the characteristic domain was first identified) encode two 60 amino acid cysteine and histidine-rich LIM domains and a homeodomain. The LIM domains function in protein-protein interactions and can bind zinc molecules. LIM domain proteins are found in both the cytosol and the nucleus. They function in cytoskeletal remodeling, at focal adhesion sites, as scaffolds for protein complexes, and as transcription factors. Most Pax genes contain
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1312-416: The many homeobox genes found in eukaryotes. Comparison of homeobox genes and gene clusters has been used to understand the evolution of genome structure and body morphology throughout metazoans. Hox genes are the most commonly known subset of homeobox genes. They are essential metazoan genes that determine the identity of embryonic regions along the anterior-posterior axis. The first vertebrate Hox gene
1353-434: The minor groove. The recognition helix and the inter-helix loops are rich in arginine and lysine residues, which form hydrogen bonds to the DNA backbone. Conserved hydrophobic residues in the center of the recognition helix aid in stabilizing the helix packing. Homeodomain proteins show a preference for the DNA sequence 5'-TAAT-3'; sequence-independent binding occurs with significantly lower affinity. The specificity of
1394-710: The opposite effect of suppressing EC migration and angiogenesis, and stabilizing adherens junctions by upregulating TIMP1/downregulating uPAR and MMP14, and by upregulating Tsp2/downregulating VEGFR2, Efna1, Hif1alpha and COX-2, respectively. HoxA5 also upregulates the tumor suppressor p53 and Akt1 by downregulation of PTEN. Suppression of HoxA5 has been shown to attenuate hemangioma growth. HoxA5 has far-reaching effects on gene expression, causing ~300 genes to become upregulated upon its induction in breast cancer cell lines. HoxA5 protein transduction domain overexpression prevents inflammation shown by inhibition of TNFalpha-inducible monocyte binding to HUVECs. LIM genes (named after
1435-751: The optic vesicle and subsequent eye structures. Proteins containing a POU region consist of a homeodomain and a separate, structurally homologous POU domain that contains two helix-turn-helix motifs and also binds DNA. The two domains are linked by a flexible loop that is long enough to stretch around the DNA helix, allowing the two domains to bind on opposite sides of the target DNA, collectively covering an eight-base segment with consensus sequence 5'-ATGCAAAT-3'. The individual domains of POU proteins bind DNA only weakly, but have strong sequence-specific affinity when linked. The POU domain itself has significant structural similarity with repressors expressed in bacteriophages , particularly lambda phage . As in animals,
1476-516: The plant homeobox genes code for the typical 60 amino acid long DNA-binding homeodomain or in case of the TALE (three amino acid loop extension) homeobox genes for an atypical homeodomain consisting of 63 amino acids. According to their conserved intron–exon structure and to unique codomain architectures they have been grouped into 14 distinct classes: HD-ZIP I to IV, BEL, KNOX, PLINC, WOX, PHD, DDT, NDX, LD, SAWADEE and PINTOX. Conservation of codomains suggests
1517-531: The regulation of patterns of anatomical development ( morphogenesis ) in animals , fungi , plants , and numerous single cell eukaryotes . Homeobox genes encode homeodomain protein products that are transcription factors sharing a characteristic protein fold structure that binds DNA to regulate expression of target genes. Homeodomain proteins regulate gene expression and cell differentiation during early embryonic development, thus mutations in homeobox genes can cause developmental disorders. Homeosis
1558-416: The single most galvanizing experience I had in terms of defining my future goals"), and cites fellow scientists Eric Davidson , Peter Lawrence and Christiane Nusslein-Volhard as "mentors [and] friends ... over the years". On choosing to become a research biologist, he described some family pressure to become a doctor ("Coming from a modest background, particularly a Jewish family, the pressure to become
1599-473: The trio identified eight genes, which turned out to be the eight homeotic genes in flies. "That pissed off a lot of people," says Levine. "The homeotic genes were the trophies of the Drosophila genome . And we got 'em all. I mean, we got 'em all!" Far from being humble, Levine says, "We were like, 'We kicked your ass pretty good, didn't we, baby!' Those were the days." Levine briefly returned to UC Berkeley as
1640-402: Was first identified in a number of Drosophila homeotic and segmentation proteins, but is now known to be well-conserved in many other animals, including vertebrates . The existence of homeobox genes was first discovered in Drosophila by isolating the gene responsible for a homeotic transformation where legs grow from the head instead of the expected antennae. Walter Gehring identified
1681-576: Was isolated in Xenopus by Edward De Robertis and colleagues in 1984. The main interest in this set of genes stems from their unique behavior and arrangement in the genome. Hox genes are typically found in an organized cluster. The linear order of Hox genes within a cluster is directly correlated to the order they are expressed in both time and space during development. This phenomenon is called colinearity. Mutations in these homeotic genes cause displacement of body segments during embryonic development. This