Antonio J. Giraldez

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Antonio Jesus Giraldez (born 1975) is a Spanish developmental biologist and RNA researcher at Yale University School of Medicine, where he serves as chair of the department of genetics and Fergus F. Wallace Professor of Genetics. He is also affiliated with the Yale Cancer Center and the Yale Stem Cell Center.

Contents

Giraldez specializes in understanding how a newly fertilized egg transforms into a highly-functioning, complex animal. This is a critical period in embryonic development and many of the pathways and molecules that drive this transformation are shared across animal species. Giraldez uses zebrafish as a model system, because it can be easily manipulated and visualized, and because the genetic tools to unlock its secrets are very sophisticated. When an egg is fertilized, it must shut down the maternal signals that maintain its identity and activate a new program to become a healthy zygote, which in turn can develop into a fully-fledged adult. Giraldez has contributed to characterizing the shift that occurs after the embryo interprets and shuts down the maternal program and activates the developmental program contained in its own genome.

Giraldez's work has wide implications for understanding developmental genetics in humans and other species, advancing RNA biology, and exploring the activation of embryonic cells in health and disease. He has been named a Howard Hughes Faculty Scholar [1] and a Pew Scholar in Biomedical Sciences. In addition, he has received the Blavatnik Award for Young Scientists (National Finalist), the Vilcek Prize for Creative Promise in Biomedical Science and the John Kendrew Young Scientist Award from the European Molecular Biology Laboratory (EMBL). [2]

Early life and education

Born in 1975 in Jerez de la Frontera, Spain, Giraldez attended high school at La Salle Buen Pastor, in Jerez de la Frontera, Spain. He followed on with studies in Chemistry and Molecular Biology at the University of Cadiz and the University Autonoma of Madrid. As an undergraduate, he worked with Ginés Morata at the Centro de Biologia Molecular Severo Ochoa (CBMSO) in Madrid. Giraldez completed his PhD with Stephen Cohen at the European Molecular Biology Laboratory (EMBL, Heidelberg, 1998–2002), followed by postdoctoral studies with Alexander Schier at the Skirball Institute (NYU) and Harvard (2003–2006).

Career

He established his laboratory at Yale in 2007, became director of graduate studies in 2012, and left that position to become chair the genetics department in 2017, where he is now the Fergus F. Wallace Professor of Genetics.

Research

Giraldez began his career at the Centro de Biologia Molecular Severo Ochoa (CBMSO) in Madrid, working on the development of Drosophila under the mentorship of Ginés Morata. He then moved to the EMBL to study the mechanisms of development of the Drosophila wing under the mentorship of Stephen Cohen. Giraldez identified the gene Notum, so called because it caused duplication of the notum region upon overexpression in the wing primordium. [3] He discovered that Notum encodes a secreted inhibitor that reduces the local concentration of an important developmental signaling molecule known as Wingless.

During his postdoctoral career at the Skirball Institute (NYU) and Harvard with Alexander Schier, Giraldez investigated the role of microRNAs and the microRNA processing machinery Dicer in vertebrate embryonic development. Giraldez's studies of mRNA and embryonic microRNAs led to fundamental insights into the mechanisms by which a maternal cell transitions to a self-regulating zygote, a process known as the maternal to zygotic transition (MZT). During MZT, zygotic genome activation regulates maternal mRNAs, but the molecular effectors of this regulation were a mystery. Giraldez and collaborators identified a conserved microRNA, miR-430 which represses, deadenylates, and clears ≈20% of maternal mRNAs2. MiR-430 is a large microRNA family that is conserved in other vertebrates: miR-427 in Xenopus and miR-290-295/302 in mouse and humans. This work, which was reported in the journal Science in 2005 and 2006, revealed the importance of miRNAs generally in different aspects of embryonic development and revealed a novel mechanism of miRNA-mediated regulation known as deadenylation. [4] [5] In 2012, Giraldez led a study showing how miR-430 reduces translation before causing mRNA decay, which was again published in Science. [6] Giraldez's work on miR-430 has opened a new area of research in the field of developmental genetics.

When Giraldez established his laboratory at Yale he continued to investigate the regulatory code that shapes embryonic development, using zebrafish as a model. In the early days of his laboratory he discovered a new mechanism of microRNA processing independent of Dicer that requires the catalytic activity of Argonaute 2, a type of Argonaute protein. [7] This pathway is required to process miR-451 in vertebrates to regulate development and cellular responses to stress during hematopoiesis. [7] [8] His work also defined hundreds of targets for different microRNAs during embryonic development, demonstrating that microRNAs can shape gene expression patterns in space and time [9] [10]

The Giraldez laboratory has applied genomic approaches to understand translation regulation during development. Using ribosome footprinting, the lab has identified novel, translated genes that encode micropeptides, one of which regulates cell motility in embryogenesis as shown by the Alexander Schier [11] [12] and Bruno Reversade [13] laboratories. Through further analysis of translation, Giraldez's work uncovered an important role for codon composition and translation in regulating mRNA stability during the maternal-to-zygotic transition across different species. [14] This regulatory layer must be conserved, based on its previous discovery in yeast by the Jeff Coller laboratory. [15] Giraldez's work established the concept that mRNAs can have differential stability dependent on the codon composition and tRNA availability [16] [17] and showed the importance of regulating mRNA levels during cellular transitions and homeostasis.

Further work in the Giraldez laboratory has explored the mechanisms of zygotic genome activation after fertilization. [18] His lab identified a set of transcription factors that enabled activation of miR-430 and a large fraction of the genome after fertilization: maternal Nanog, Oct4 and SoxB1. [19] Some of these factors are involved in stem cell maintenance and cellular reprogramming. [20] These findings offer a new understanding of how the genome becomes activated, linking cellular and developmental reprogramming.

Giraldez's current work involves deciphering the post-transcriptional regulatory code during development and the regulation of cellular differentiation in the zygote. In 2018, Giraldez delivered a Keynote Lecture as part of Cold Spring Harbor Laboratory's Leading Strand Series, which can be viewed online here.

Professional activities

Giraldez has served on several major review committees. In addition to being a permanent member of the NIH Dev1 Study Section, he has served on the Pew Scholars Alumni Review Board and the Damon Runyon Cancer Research Foundation Fellowship Awards Committee.

Awards and honors

Personal life

Giraldez is married to fellow faculty member Valentina Greco.

Related Research Articles

<span class="mw-page-title-main">Zebrafish</span> Species of fish

The zebrafish is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio. It is also found in private ponds.

microRNA Small non-coding ribonucleic acid molecule

MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRNAs base-pair to complementary sequences in mRNA molecules, then gene silence said mRNA molecules by one or more of the following processes: (1) cleavage of mRNA strand into two pieces, (2) destabilization of mRNA by shortening its poly(A) tail, or (3) translation of mRNA into proteins. This last method of gene silencing is the least efficient of the three, and requires the aid of ribosomes.

An oocyte, oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female germ cells produce a primordial germ cell (PGC), which then undergoes mitosis, forming oogonia. During oogenesis, the oogonia become primary oocytes. An oocyte is a form of genetic material that can be collected for cryoconservation.

<i>Drosophila</i> embryogenesis Embryogenesis of the fruit fly Drosophila, a popular model system

Drosophila embryogenesis, the process by which Drosophila embryos form, is a favorite model system for genetics and developmental biology. The study of its embryogenesis unlocked the century-long puzzle of how development was controlled, creating the field of evolutionary developmental biology. The small size, short generation time, and large brood size make it ideal for genetic studies. Transparent embryos facilitate developmental studies. Drosophila melanogaster was introduced into the field of genetic experiments by Thomas Hunt Morgan in 1909.

Hox genes, a subset of homeobox genes, are a group of related genes that specify regions of the body plan of an embryo along the head-tail axis of animals. Hox proteins encode and specify the characteristics of 'position', ensuring that the correct structures form in the correct places of the body. For example, Hox genes in insects specify which appendages form on a segment, and Hox genes in vertebrates specify the types and shape of vertebrae that will form. In segmented animals, Hox proteins thus confer segmental or positional identity, but do not form the actual segments themselves.

In developmental biology, midblastula or midblastula transition (MBT) occurs during the blastula stage of embryonic development in non-mammals. During this stage, the embryo is referred to as a blastula. The series of changes to the blastula that characterize the midblastula transition include activation of zygotic gene transcription, slowing of the cell cycle, increased asynchrony in cell division, and an increase in cell motility.

mir-10 microRNA precursor family

The miR-10 microRNA precursor is a short non-coding RNA gene involved in gene regulation. It is part of an RNA gene family which contains miR-10, miR-51, miR-57, miR-99 and miR-100. miR-10, miR-99 and miR-100 have now been predicted or experimentally confirmed in a wide range of species. mir-51 and mir-57 have currently only been identified in the nematode Caenorhabditis elegans.

mir-129 microRNA precursor family

The miR-129 microRNA precursor is a small non-coding RNA molecule that regulates gene expression. This microRNA was first experimentally characterised in mouse and homologues have since been discovered in several other species, such as humans, rats and zebrafish. The mature sequence is excised by the Dicer enzyme from the 5' arm of the hairpin. It was elucidated by Calin et al. that miR-129-1 is located in a fragile site region of the human genome near a specific site, FRA7H in chromosome 7q32, which is a site commonly deleted in many cancers. miR-129-2 is located in 11p11.2.

mir-133 microRNA precursor family

mir-133 is a type of non-coding RNA called a microRNA that was first experimentally characterised in mice. Homologues have since been discovered in several other species including invertebrates such as the fruitfly Drosophila melanogaster. Each species often encodes multiple microRNAs with identical or similar mature sequence. For example, in the human genome there are three known miR-133 genes: miR-133a-1, miR-133a-2 and miR-133b found on chromosomes 18, 20 and 6 respectively. The mature sequence is excised from the 3' arm of the hairpin. miR-133 is expressed in muscle tissue and appears to repress the expression of non-muscle genes.

mir-199 microRNA precursor

The miR-199 microRNA precursor is a short non-coding RNA gene involved in gene regulation. miR-199 genes have now been predicted or experimentally confirmed in mouse, human and a further 21 other species. microRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product. The mature products are thought to have regulatory roles through complementarity to mRNA.

mir-19 microRNA precursor family

There are 89 known sequences today in the microRNA 19 (miR-19) family but it will change quickly. They are found in a large number of vertebrate species. The miR-19 microRNA precursor is a small non-coding RNA molecule that regulates gene expression. Within the human and mouse genome there are three copies of this microRNA that are processed from multiple predicted precursor hairpins:

The miR-34 microRNA precursor family are non-coding RNA molecules that, in mammals, give rise to three major mature miRNAs. The miR-34 family members were discovered computationally and later verified experimentally. The precursor miRNA stem-loop is processed in the cytoplasm of the cell, with the predominant miR-34 mature sequence excised from the 5' arm of the hairpin.

The Nodal signaling pathway is a signal transduction pathway important in regional and cellular differentiation during embryonic development.

Joshua T. Mendell, M.D., Ph.D., is a professor of molecular biology at the University of Texas Southwestern Medical Center, where he is a Howard Hughes Medical Institute Investigator. Before moving to UT Southwestern, Mendell was a Howard Hughes Medical Institute early career scientist at Johns Hopkins School of Medicine. His molecular biology research examines microRNA (miRNA) regulation and function, with particular emphasis on miRNAs and cancer.

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.

In molecular biology mir-430 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

<span class="mw-page-title-main">Alexander F. Schier</span> Swiss biologist

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<span class="mw-page-title-main">Smaug (protein)</span> RNA-binding protein in Drosophila

Smaug is a RNA-binding protein in Drosophila that helps in maternal to zygotic transition (MZT). The protein is named after the fictional character Smaug, the dragon in J.R.R. Tolkien's 1937 novel The Hobbit. The MZT ends with the midblastula transition (MBT), which is defined as the first developmental event in Drosophila that depends on zygotic mRNA. In Drosophila, the initial developmental events are controlled by maternal mRNAs like Hsp83, nanos, string, Pgc, and cyclin B mRNA. Degradation of these mRNAs, which is expected to terminate maternal control and enable zygotic control of embryogenesis, happens at interphase of nuclear division cycle 14. During this transition smaug protein targets the maternal mRNA for destruction using miRs. Thus activating the zygotic genes. Smaug is expected to play a role in expression of three miRNAs – miR-3, miR-6, miR-309 and miR-286 during MZT in Drosophila. Among them smaug dependent expression of miR-309 is needed for destabilization of 410 maternal mRNAs. In smaug mutants almost 85% of maternal mRNA is found to be stable. Smaug also binds to 3′ untranslated region (UTR) elements known as SMG response elements (SREs) on nanos mRNA and represses its expression by recruiting a protein called Cup(an eIF4E-binding protein that blocks the binding of eIF4G to eIF4E). There after it recruits deadenylation complex CCR4-Not on to the nanos mRNA which leads to deadenylation and subsequent decay of the mRNA. It is also found to be involved in degradation and repression of maternal Hsp83 mRNA by recruiting CCR4/POP2/NOT deadenylase to the mRNA. The human Smaug protein homologs are SAMD4A and SAMD4B.

<span class="mw-page-title-main">Howard Lipshitz</span>

Howard David Lipshitz is an American and Canadian biologist who does genetic research on the fruit fly, Drosophila.

References

  1. ↑ "Faculty Scholars Program HHMI".
  2. ↑ "Winner of the John Kendrew Young Scientist Award".
  3. ↑ HSPG modification by the secreted enzyme Notum shapes the Wingless morphogen gradient. Giráldez AJ, Copley RR, Cohen SM. Dev Cell. 2002 May;2(5):667-76.
  4. ↑ Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Giraldez AJ, Mishima Y, Rihel J, Grocock RJ, Van Dongen S, Inoue K, Enright AJ, Schier AF. Science. 2006 Apr 7;312(5770):75-9. Epub 2006 Feb 16
  5. ↑ MicroRNAs regulate brain morphogenesis in zebrafish. Giraldez AJ, Cinalli RM, Glasner ME, Enright AJ, Thomson JM, Baskerville S, Hammond SM, Bartel DP, Schier AF. Science. 2005 May 6;308(5723):833-8. Epub 2005 Mar 17.
  6. ↑ Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish. Bazzini AA, Lee MT, Giraldez AJ. Science. 2012 Apr 13;336(6078):233-7. Doi: 10.1126/science.1215704. Epub 2012 Mar 15
  7. 1 2 A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Cifuentes D, Xue H, Taylor DW, Patnode H, Mishima Y, Cheloufi S, Ma E, Mane S, Hannon GJ, Lawson ND, Wolfe SA, Giraldez AJ. Science. 2010 Jun 25;328(5986):1694-8. doi: 10.1126/science.1190809. Epub 2010 May 6
  8. ↑ A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Cheloufi S, Dos Santos CO, Chong MM, Hannon GJ. Nature. 2010 Jun 3;465(7298):584-9. doi: 10.1038/nature09092
  9. ↑ Zebrafish miR-1 and miR-133 shape muscle gene expression and regulate sarcomeric actin organization. Mishima Y, Abreu-Goodger C, Staton AA, Stahlhut C, Shou C, Cheng C, Gerstein M, Enright AJ, Giraldez AJ. Genes Dev. 2009
  10. ↑ Differential regulation of germline mRNAs in soma and germ cells by zebrafish miR-430. Mishima Y, Giraldez AJ, Takeda Y, Fujiwara T, Sakamoto H, Schier AF, Inoue K. Curr Biol. 2006 Nov 7;16(21):2135-42.
  11. ↑ Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Pauli A, Norris ML, Valen E, Chew GL, Gagnon JA, Zimmerman S, Mitchell A, Ma J, Dubrulle J, Reyon D, Tsai SQ, Joung JK, Saghatelian A, Schier AF. Science. 2014 Feb 14;343(6172):1248636. doi: 10.1126/science.1248636. Epub 2014 Jan 9.
  12. ↑ Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling. Norris ML, Pauli A, Gagnon JA, Lord ND, Rogers KW, Mosimann C, Zon LI, Schier AF. Elife. 2017 Nov 9;6. pii: e22626. doi: 10.7554/eLife.22626
  13. ↑ The hormonal peptide Elabela guides angioblasts to the midline during vasculogenesis. Helker CS, Schuermann A, Pollmann C, Chng SC, Kiefer F, Reversade B, Herzog W. Elife. 2015 May 27;4. doi: 10.7554/eLife.06726.
  14. ↑ Codon identity regulates mRNA stability and translation efficiency during the maternal-to-zygotic transition. Bazzini AA, Del Viso F, Moreno-Mateos MA, Johnstone TG, Vejnar CE, Qin Y, Yao J, Khokha MK, Giraldez AJ. EMBO J. 2016 Oct 4;35(19):2087-2103. Epub 2016 Jul 19.
  15. ↑ Codon optimality is a major determinant of mRNA stability. Presnyak V, Alhusaini N, Chen YH, Martin S, Morris N, Kline N, Olson S, Weinberg D, Baker KE, Graveley BR, Coller J. Cell. 2015 Mar 12;160(6):1111-24. doi: 10.1016/j.cell.2015.02.029.
  16. ↑ Codon optimality, bias and usage in translation and mRNA decay. Hanson G, Coller J. Nat Rev Mol Cell Biol. 2018 Jan;19(1):20-30. doi: 10.1038/nrm.2017.91. Epub 2017 Oct 11. Review.
  17. ↑ Starting too soon: upstream reading frames repress downstream translation. McGeachy AM, Ingolia NT. EMBO J. 2016 Apr 1;35(7):699-700. doi: 10.15252/embj.201693946. Epub 2016 Feb 19.
  18. ↑ Zygotic genome activation during the maternal-to-zygotic transition. Lee MT, Bonneau AR, Giraldez AJ. Annu Rev Cell Dev Biol. 2014;30:581-613. doi: 10.1146/annurev-cellbio-100913-013027. Epub 2014 Aug 11. Review.
  19. ↑ Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to-zygotic transition. Lee MT, Bonneau AR, Takacs CM, Bazzini AA, DiVito KR, Fleming ES, Giraldez AJ. Nature. 2013 Nov 21;503(7476):360-4. doi: 10.1038/nature12632. Epub 2013 Sep 22.
  20. ↑ A developmental framework for induced pluripotency. Takahashi K, Yamanaka S. Development. 2015 Oct 1;142(19):3274-85. doi: 10.1242/dev.114249. Review.
  1. ↑ Antonio Giraldez: at the tip of the microRNA iceberg. Giraldez A. J Cell Biol. 2009 Jun 29;185(7):1132-3. doi: 10.1083/jcb.1857pi.
  2. ↑ Yale Scientists Track the Development of the Embryo. Hathaway, B. Sci Tech Daily. 2017 Feb. https://scitechdaily.com/yale-scientists-track-the-development-of-the-embryo/
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