Loading ...
Sorry, an error occurred while loading the content.

Evolution of Genetic Networks Underlying the Emergence of Thymopoiesis in Verteb

Expand Messages
  • Eric
    Nature 460, 14-15 (2 July 2009) Evolution of Genetic Networks Underlying the Emergence of Thymopoiesis in Vertebrates Baubak Bajoghli1
    Message 1 of 1 , Jul 1, 2009
    • 0 Attachment
      Nature 460, 14-15 (2 July 2009)

      Evolution of Genetic Networks Underlying the Emergence of Thymopoiesis
      in Vertebrates

      Baubak Bajoghli1
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff1aff1> , 6
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#fn3fn3> , Narges Aghaallaei1
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff1aff1> , 6
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#fn3fn3> , Isabell Hess1
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff1aff1> , 6
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#fn3fn3> , Immanuel Rode1
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff1aff1> , Nikolai Netuschil1
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff1aff1> , Boon-Hui Tay2
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff2aff2> , Byrappa Venkatesh2
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff2aff2> , Jr-Kai Yu3
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff3aff3> , 4
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#fn1fn1> , Stacy L. Kaltenbach3
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff3aff3> , 5
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#fn2fn2> , Nicholas D. Holland3
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff3aff3> , Dagmar Diekhoff1
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff1aff1> , Christiane Happe1
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff1aff1> , Michael Schorpp1
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff1aff1> and Thomas Boehm1
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#aff1aff1> ,

      1Department of Developmental Immunology, Max-Planck Institute of
      Immunobiology, Stuebeweg 51, D-79108 Freiburg, Germany

      2Institute of Molecular and Cell Biology, Agency for Science,
      Technology, and Research (A*STAR), Biopolis, Singapore 138673, Republic
      of Singapore

      3Marine Biology Research Division, Scripps Institution of Oceanography,
      University of California San Diego, La Jolla, CA 92093-0202, USA


      Received 10 December 2008;

      revised 2 March 2009;

      accepted 3 April 2009.

      Published online: June 25, 2009.

      Available online 25 June 2009.



      Summary

      About 500 million years ago, a new type of adaptive immune defense
      emerged in basal jawed vertebrates, accompanied by morphological
      innovations, including the thymus. Did these evolutionary novelties
      arise de novo or from elaboration of ancient genetic networks? We
      reconstructed the genetic changes underlying thymopoiesis by comparative
      genome and expression analyses in chordates and basal vertebrates. The
      derived models of genetic networks were experimentally verified in bony
      fishes. Ancestral networks defining circumscribed regions of the
      pharyngeal epithelium of jawless vertebrates expanded in cartilaginous
      fishes to incorporate novel genes, notably those encoding chemokines.
      Correspondingly, novel networks evolved in lymphocytes of jawed
      vertebrates to control the expression of additional chemokine receptors.
      These complementary changes enabled unprecedented Delta/Notch signaling
      between pharyngeal epithelium and lymphoid cells that was exploited for
      specification to the T cell lineage. Our results provide a framework
      elucidating the evolution of key features of the adaptive immune system
      in jawed vertebrates.

      Introduction

      Adaptive immune systems provide anticipatory, clonally distributed,
      diverse, and self-tolerant repertoires of antigen receptors for immune
      defense. To date, adaptive immune systems have only been described in
      vertebrates (Cooper and Alder, 2006
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib19> ).
      Interestingly, adaptive immune systems appear to have independently
      arisen twice in basal vertebrates, once in the lineage that gave rise to
      jawless vertebrates, with hagfish and lamprey as their surviving
      representatives, and a second time in the lineage giving rise to all
      jawed vertebrates, with cartilaginous fishes (sharks, rays, skates, and
      so-called chimaeras) as their most ancestral extant forms. Jawless
      vertebrates utilize gene conversion (Nagawa et al., 2007
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib35> ) to
      generate diversity of their variable lymphocyte receptors (Pancer et
      al., 2004
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_ac\
      ct=C000047781&_version=1&_urlVersion=0&_userid=907668&md5=3c9ff441ae5a7e\
      88887c6b2bee1bf0af#bbib38> Z. Pancer, C.T. Amemiya, G.R.A. Ehrhardt, J.
      Ceitlin, G.L. Gartland and M.D. Cooper, Somatic diversification of
      variable lymphocyte receptors in the agnathan sea lamprey, Nature 430
      (2004), pp. 174–180. Full Text via CrossRef
      <http://www.sciencedirect.com/science?_ob=RedirectURL&_method=outwardLin\
      k&_partnerName=3&_targetURL=http%3A%2F%2Fdx.doi.org%2F10.1038%2Fnature02\
      740&_acct=C000047781&_version=1&_userid=907668&md5=a3d8bbe813210dba9cef4\
      81d128671df> Pancer et al., 2004
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib38> ),
      while jawed vertebrates employ the so-called VDJ recombination (Schatz,
      2004
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib49> ) in
      developing lymphocytes to achieve combinatorial diversity of
      immunoglobulins and T cell receptors respectively (Litman and Cooper,
      2007
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib33> ). The
      fundamental differences in the mechanisms of recombination and the
      molecular nature of receptor structures highlight the independent
      origins of these two types of adaptive immune systems. Yet, both types
      of rearranging systems function in lymphocytes, suggesting that the
      common ancestor of vertebrates possessed lymphocytes but no adaptive
      immune system. The adaptive immune system of jawed vertebrates emerged
      in cartilaginous fishes about 500 million years ago. In addition to the
      primordial myelolymphoid lineage of lymphocytes (Kawamoto, 2006
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib28> ), the
      adaptive immune system of jawed vertebrates is distinguished by the
      emergence of T cells as a novel lymphocyte lineage, and the thymus as a
      primary lymphoid organ (Boehm and Bleul, 2007
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib14> ).
      Functionally, T cells and thymus are inextricably linked, for without
      the latter, T cell development fails.

      Thymopoiesis is a complex process involving colonization of the
      epithelial organ anlage by lymphoid progenitor cells (Bhandoola et al.,
      2007
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib8> ),
      commitment of these progenitors to the T cell lineage ([Hozumi et al.,
      2008]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib24> and
      [Koch et al., 2008]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib30> ), and
      their subsequent differentiation, including tolerance induction
      (Anderson et al., 2007
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib4> ).
      Differentiation of the prospective thymic epithelium in the pharyngeal
      endoderm (Rodewald, 2008
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib43> )
      critically depends on the function of the transcription factor Foxn1
      (Nehls et al., 1996
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib36> ).
      Mutations in the Foxn1 gene are associated with a failure of
      thymopoiesis owing to a nonfunctional epithelial microenvironment
      ([Blackburn et al., 1996]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib9> and
      [Nehls et al., 1996]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib36> ),
      which lacks expression of chemokine genes ([Bleul and Boehm, 2000]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib10> and
      [Itoi et al., 2007]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib25> ) that
      are thought to be important for attraction of lymphoid progenitors
      (Bleul and Boehm, 2000
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib10> ) and
      delta-like genes (Itoi et al., 2007
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib25> )
      required for their specification toward the T cell lineage ([Hozumi et
      al., 2008]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib24> and
      [Koch et al., 2008]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib30> ).
      Furthermore, Foxn1 is required for the differentiation of epithelial
      progenitor cells (Bleul et al., 2006
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib11> ) into
      all subsets of the thymic epithelium, including those defining the
      cortex and the medulla ([Bleul et al., 2006]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib11> and
      [Rossi et al., 2006]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib44> ).
      These observations indicate that Foxn1 occupies a key position in the
      genetic network(s) establishing a functional thymic niche, which is
      essential for T cell development. Many genes are important for the early
      development of T cells, including, among others, Notch1, Rbpj, Gata3,
      Ikaros, and Bcl11b (for review, see Rothenberg et al., 2008
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib45> ),
      although their individual contributions to the sequential steps of T
      cell development are not always well documented. B cell development
      appears to be the default pathway of differentiation for lymphoid
      progenitor cells, unless Notch signaling (through Notch1 receptors;
      Radtke et al. [2004]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib40> )
      occurs in the thymic epithelial anlage, which expresses Dll4 as the
      essential and non-redundant ligand for T cell specification ([Hozumi et
      al., 2008]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib24> and
      [Koch et al., 2008]
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib30> ).
      These observations support earlier suggestions that antibody-producing
      myelolymphoid cells might represent the primordial phenotype of the
      vertebrate lymphocyte lineage (Kawamoto, 2006
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib28> ) and
      that the T cell lineage emerged at a later point (Boehm and Bleul, 2007
      <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10PH-\
      1&_user=907668&_coverDate=06%2F25%2F2009&_rdoc=1&_fmt=full&_orig=search&\
      _cdi=7051&_sort=d&_docanchor=&view=c&_acct=C000047781&_version=1&_urlVer\
      sion=0&_userid=907668&md5=6ea872fb94bc4c3c21025812183ab00c#bib14> ).
      Unfortunately, neither jawless nor cartilaginous fishes, which occupy
      key phylogenetic positions with respect to the evolution of adaptive
      immune systems, are amenable to genetic analysis. Therefore, the
      elucidation of the genetic changes underlying the emergence of
      thymopoiesis poses a formidable challenge; yet, such studies might
      provide essential information for the understanding of cellular
      immunity. We set out to reconstruct the evolutionary origins of
      thymopoiesis, employing the following strategy. First, we analyzed the
      genomes of several key chordate and vertebrate species in order to trace
      the evolutionary history of genes potentially involved in the emergence
      of thymopoiesis. Second, we determined their possible coexpression in
      order to derive models of potential genetic interactions. Finally, we
      tested these predictions in bony fishes to validate the structure of
      relevant genetic networks. Our results indicate how in jawed
      vertebrates, ancient genetic networks in pharyngeal epithelium and
      lymphocytes increased in complexity and how these novel functionalities
      enabled unprecedented cellular interactions between these two cell
      types. We suggest that these key advances provided the basis for the
      evolution of T cells and the thymus.



      SEE FULL ARTICLE:





      Cell doi:10.1016/j.cell.2009.04.017 (2009)
      <http://dx.doi.org/10.1016/j.cell.2009.04.017>



      [Non-text portions of this message have been removed]
    Your message has been successfully submitted and would be delivered to recipients shortly.