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Homeobox Genes

Homeobox Genes. Body Patterning. Body plans. Every organism has a unique body pattern because of the influence of homeobox genes.

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Homeobox Genes

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  1. Homeobox Genes Body Patterning

  2. Body plans • Every organism has a unique body pattern because of the influence of homeobox genes. • Homeoboxgenes were discovered when geneticists studying fruit flies found mutants with legs growing where their antennae should be and 2 sets of wings instead of 1.

  3. Homeotic Genes • Homeotic genes are regulatory genes that determine where certain anatomical structures, such as appendages, will develop in an organism during morphogenesis. • These seem to be the master genes of development Mutant with legs growing out of head Normal

  4. Homeotic genes encode homeotic proteins that function as transcription factorswhich switch on other genes The Homeobox is a coding sequence within homeotic genes which contains 180 base-pair sequences, codes for 60 amino acid polypeptide Encodes homeodomainfor DNA binding

  5. Homeobox (HOX genes) The Hox proteins regulate other “executive” genes that encode transcription factors or morphogen signals, as well as operating at many other levels, on genes that mediate cell adhesion, cell division rates, cell death and cell movement.

  6. Hox genes • Twolines of evidence support the idea that Hoxgene complexity has been instrumental in the evolution and speciation of animals with different body patterns • Hox genes are known to control body development • Simpleranimals to have fewer Hox genes and Hox gene clusters

  7. Fruit flies have only one Antennepedia-bithorax complex • Humans and many other vertebrates have 4 similar Hox gene clusters • They probably arose through gene duplication • Hox genes shape the number and appearance of body segments (repeated structures) along the main body axes of both vertebrates and invertebrates

  8. Antennapedia complex (group of Homeobox genes) • 5 genes that affect the anterior part of the fly • When mutated, legs grow instead of antennae

  9. Bithorax gene complex (3 homeobox genes affecting thoracic development) • Normal – wings on 2nd thoracic segment and 2 halteres on 3rd thoracic segment • Mutant – 3rd segment has wings so 2 sets of wings and no halteres

  10. Hox gene clusters: Homeotic selector genes • Hox genes are present and expressed in similar patterns in nearly every Bilateral animal. • Hoxgene clusters, which were originally called homeotic selector genes.

  11. Homeotic Transformation • Ranging from nematodes to mice, mutations in Hox genes result in morphological defects that are restricted to discretesegmental zones along the anterior–posterior (A–P) axis, and sometimes include homeotic transformations. • Homeotic transformation: The transformation of one body region into the likeness of another.

  12. Hox-response Enhancers • The homeodomain transcription factors that are encoded by the Hox genes activate and repress batteries of downstream genes by directly binding to DNAsequences in Hox-response enhancers.

  13. Hox-response Enhancers • On many target enhancers, Hox proteins cooperatively bind to canonical heterodimer-binding sites with EXD members of the PBC family of homeodomainproteins and binding sites for the HTH super-family of homeodomain proteins in D.melanogaster.

  14. Hox response elements function

  15. Ref.1

  16. Hox regulation: executive level • One executive target gene is decapentaplegic (dpp), which is expressed in an A–P domain of visceral mesoderm in D.melanogaster. • Ultrabithorax (UBX) and Abdominal-A (ABD-A) Hox proteins provide this dpp expression pattern to activate and repress dpp transcription.

  17. Also Ultrabithorax (UBX) directly repress the Distal-less (Dll) gene in the abdominal epidermis that results absence of limbs from the abdomen. The Dll gene encodes a homeodomain transcription factor that promotes appendage development.

  18. Hox regulation: cell death • In D.melanogaster embryos, maintenance of the segmental boundary between the maxillary and mandibular segments of the head requires localized cell death at the boundary that is controlled by the apoptosis-promoting gene reaper (rpr).

  19. That shows basicly why the abdominal CNS is much smaller than the thoracic CNS.

  20. Validation of direct target elements of Hox target enhancers If the altered protein regains the ability to regulate the altered enhancer, specific Hox protein can bind to a specific enhancer in embryonic cells.

  21. Tissue Specificity • The UBX-dependent enhancer from Drosophila dpp is active only in the visceral mesoderm, and is inactive in the epidermal, CNS and somatic mesoderm cells that also contain UBX protein. • (dpp enhancer regulated by a visceral-mesoderm-specific forkhead-type transcription factor (Biniou/FOXF))

  22. Another example for tissue specificity by two autoactivation enhancers: Dfd protein autoactivates Dfd transcription in the CNS. That is mediated by second enhancer which maps to the large intron of the Dfd gene

  23. Hox genes and morphological evolution (Carroll,S.B. et al and Ronshaugen,M. et al)

  24. Hox genes and morphological evolution • Hox expression-pattern change and Hox-protein-function change take evolutionary origin from bicoid (bcd), zerknullt (zen), fushi tarazu (ftz) and even skipped (eve) genes in D.melanogaster. • Control of early embryonic polarity (bcd) • Segment number (ftz and eve)

  25. The evolution of ftz from a Hox5/6-like gene In many arthropod embryos including some insects ftz expression from Hox5/6-like gene Undergo mutations (YWPM to LXXLL) Flies and Beetles Segment number (+) Segment Identity (-) Alters the ancestral ftz protein Lost its axial identity and gained the ability to regulate segment number

  26. References • Joseph C. Pearson, Derek Lemons and William McGinnis- Modulating Hox Gene Functions During Animal Body Patterning – Nature Reviews/Genetics – Vol 6 / December 2005 • Drosophila pattern formation: a meeting review - Genes Dev. 1988 2: 617-619 • Brian Gebelein, Daniel J. McKay & Richard S. Mann -Direct integration of Hox and segmentation gene inputs during Drosophila development – Nature / Vol 431 / 7 October 2004 • Stefanie D. Hueber, Daniela Bezdan, Stefan R. Henz, Martina Blank, Haijia Wu and Ingrid Lohmann - Comparative analysis of Hox downstream genes inDrosophila - Development 134, 381-392 (2007) • Michael T. Murtha, James F. Leckman, and Frank H. Ruddle - Detection of homeobox genes in development and evolution - Developmental Biology / Vol. 88, pp. 10711-10715, December 1991

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