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Chapter 16. The Genetic Basis of Development. 4 and 6 April, 2005. zygote  adult. Overview. Instructions in the genome establish the developmental fate of cells in multicellular organisms. Developmental pathways consist of sequences of various regulatory steps.

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Chapter 16 l.jpg

Chapter 16

The Genetic Basis of Development

4 and 6 April, 2005

zygote  adult

Overview l.jpg

  • Instructions in the genome establish the developmental fate of cells in multicellular organisms.

  • Developmental pathways consist of sequences of various regulatory steps.

  • The zygote is totipotent, giving rise to all body cells.

  • Gradients of maternally-derived regulatory proteins establish polarity of the body axis and control transcriptional activation of zygotic genes.

  • Transcriptional regulation and cell signaling mediate development in animals and plants.

  • The same set of genes appears to regulate early development in all animals.

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  • In multicellular organisms, life begins as a single cell.

  • With few exceptions, somatic cells contain the same genetic information as the zygote.

  • In development, cells commit to specific fates and differentially express subsets of genes.

  • Cells identify and respond to their position in developmental fields.

  • Daughter cells may differ with respect to regulatory instructions and developmental fate.

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Building the embryo

  • Developmental decisions

    • made at specific times during development

    • many are binary, e.g., male or female, germ line or somatic.

    • most are irreversible

    • many involve groups of cells rather than single cells

  • In animals decisions are made to

    • establish anterior-posterior and dorsal-ventral axes

    • subdivide anterior-posterior axis into segments

    • subdivide dorsal-ventral axis into germ layers

    • produce various tissues and organs

  • Most decisions involve changes in transcription

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Sex determination

  • XX-XY chromosomal systems for sex determination have evolved many times

  • Different molecular pathways for sex determination in different groups of animals

  • Drosophila

    • each cell lineage makes sexual decision

    • ratio of X chromosomes to autosomes determines sex

    • cascade of differential mRNA splicing

  • Mammals

    • TDF gene on Y chromosome determines maleness

    • endocrine hormonal system

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Sxl toggle

  • Ratio of NUM bHLH proteins to DEM bHLH proteins measures X:A ratio by competing for dimer formation

    • DNA binding domain of NUM proteins recognizes Sxl early promoter

    • twice as much NUM protein in females with two X chromosomes as males with one X results in more NUM-NUM homodimers

  • Sufficient NUM-NUM homodimers activate Sxl early promoter resulting in SXL protein that alternatively splices larger Sxl transcript from late promoter

    • sets up autoregulatory loop in flies with X:A ratio of 1.0

    • in flies with X:A ratio of 0.5, insufficient NUM-NUM homodimers results in no SXL protein and late transcript is normally processed (yields nonfunctional protein)

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Sxl downstream target

  • SXL protein activates downstream shunt that leads to female development

    • SXL protein binds to primary transcript of tra (transformer) resulting in spliced transcript that produces TRA protein

    • TRA protein in turn is RNA-binding protein that produces female-specific splicing of dsx (doublesex) transcript

    • DSX-F transcription factor represses male-specific gene expression resulting in female development

  • In absence of SXL, there is no functional TRA protein, and dsx is spliced to produce DSX-M transcription factor which represses female-specific genes, leading to male development

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Sex determination in mammals

  • Presence of Y chromosome determines maleness

    • SRY gene in humans encodes transcription factor (testis-determining factor)

    • expression of SRY in developing gonad causes it to develop into testis

    • testis secretes testosterone resulting in male development

  • In XX individuals, absence of SRY protein and subsequent absence of testosterone results in default female shunt pathway

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Role of cytoskeleton in development

  • Consists of highly organized rods and fibers

    • microfilaments (actin)

    • intermediate filaments

    • microtubules

  • Such structures are polar, with distinct “+” and “–” ends

  • Serve as highway system for intracellular transport

  • Asymmetry of cytoskeletal elements plays fundamental roles

    • location of mitotic cleavage plane

    • control of cell shape

    • directed transport of molecules

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Origin of germ line

  • In animals, germ line is set aside from soma in early development

    • only germ cells can undergo meiosis

    • somatic cells form body of organism

  • Asymmetric distribution of cytoplasmic particles (e.g., P granules of Caenorhabditis elegans) by cytoskeleton

    • cells receiving particles develop into germ line

    • particles anchored to actin in some organisms, to microtubules in others

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Drosophila anterior-posterior axis

  • Determined by gradients of BCD (product of bicoid) and HB-M (product of hunchback)

    • mRNA maternally deposited in egg

    • BCD mRNA tethered to “–” ends of microtubules via 3’ UTR

    • HB-M protein gradient depends on NOS protein

      • nos mRNA tethered to “+” end of microtubule via 3’ UTR

      • NOS protein gradient blocks translation of hb-m mRNA, resulting in HB-M gradient

  • Resulting opposite gradients of BCD and Nos determine axis

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Drosophila dorsal-ventral axis

  • Determined by gradient of transcription factor DL (encoded by dorsal)

    • gradient established by interaction of spz and Toll gene products deposited in oogenesis and released during embryogenesis

    • SPZ-TOLL complex triggers signal transduction pathway in cells that phosphorylates inactive DL

  • Phosphorylated DL migrates to nucleus, activating genes for ventral fates

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Positional information

  • Localization of mRNAs within cell establishes positional information in cases where developmental fields begin as a single cell

  • Formation of concentration gradients of extracellular diffusible molecules establishes positional information in multicellular developmental fields

    • works by signal transduction

    • diffusible molecules are known as morphogens

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Complex pattern: Drosophila

  • Successive interpretation of established, changing, and new gradients

  • Largely due to changes in transcription

  • Genes targeted by gradients of maternal A-P and D-V transcription factors are cardinal genes

    • respond to these factors at enhancers and silencers

    • similar genes in other animals

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Drosophila development (1)

  • Early syncitial development

    • zygotic nucleus divides 9 times with no cell division

      • some nuclei migrate to posterior pole to give rise to germ line

    • 4 more mitotic divisions without cell division

  • Nuclei migrate to surface of egg cytoplasm

    • membrane forms around them (cellularization)

    • begin responding to positional information in A-P and D-V transcription factor gradients.

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Drosophila development (2)

  • At 10 hours, 14 segments

    • 3 head

    • 3 thoracic

    • 8 abdominal

  • At 12 hours, organogenesis begins

  • At 15 hours, exoskeleton begins to form

  • At 24 hours, larva hatches

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Drosophila development (3)

  • Developmental fate determined through transcription-factor interactions

  • A-P cardinal genes = gap genes

    • Kruppel and knirps (mutants have gap in normal segmentation)

    • promoters have differential sensitivity to BCD and/or HB-M

    • establishes different developmental fields along embryo, roughly defining segments

  • Bifurcation of development: targets of gap gene encoded transcription factors

    • one branch to establish correct number of segments

    • one branch to assign proper identity to each segment

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Drosophila development (4)

  • Segment number

    • gap gene products activate pair-rule genes

      • several different pair-rule genes

      • expression produces repeating pattern of seven stripes, each offset

    • pair-rule products act combinatorially to regulate transcription of segment-polarity genes

      • expressed in offset pattern of 14 stripes

  • Segment identity

    • gap gene products target cluster of homeotic gene complexes

      • encode homeodomain transcription factors

      • mutations alter developmental fate of segment

    • e.g., Bithorax (posterior thorax and abdomen) and Antennapedia (head and anterior thorax)

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Pattern formation

  • Transcriptional response to gradients (asymmetrical distribution) of transcription factors

  • Memory of cell fate

    • intracellular and intercellular positive-feedback loops

    • e.g., homeodomain protein binds to enhancer elements of its own gene, ensuring continued transcription

  • Cell-cell interactions

    • inductive interaction commits groups of cells to same developmental fate

    • lateral inhibition results in neighboring cells assuming secondary fate

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  • Asymmetry of maternal gene products establishes positional information used for early development

  • Successive rounds of expression of genes encoding transcription factors establish axes and body part identity

  • Positive feedback loops maintain differentiated state

  • Components of one developmental pathway are also found in many others

  • Differences in types and concentrations of transcription factors result in different outputs

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Developmental parallels

  • Early animal development follows fundamentally similar pattern

  • Remarkable similarity among homeotic genes

    • one HOM-C cluster in insects

    • four HOX clusters in mammals

      • paralogous to insect cluster

      • expressed in segmental fashion in early development

  • Knockout and genome studies suggest animal development uses same regulatory pathways

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Development in plants

  • Plants have different organ systems than animals and plant cells can not migrate

  • Plants do not separate soma from germ-line until flower development

  • Plants too have hormones and signaling pathways

  • Arabidopsis thaliana is model system

  • Transcriptional regulators control fate of four whorls (layers) giving rise to flower

    • process similar action of homeotic genes in animal development