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17. Developmental Regulation

17. Developmental Regulation. Developmental Regulation. Many inherited diseases result from mutations in genes regulating development Treatments/therapies may be discerned by understanding regulatory mechanisms Three basic points of control: 1. Transcriptional regulation

hillary-french
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17. Developmental Regulation

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  1. 17.Developmental Regulation

  2. Developmental Regulation • Many inherited diseases result from mutations in genes regulating development • Treatments/therapies may be discerned by understanding regulatory mechanisms • Three basic points of control: 1. Transcriptional regulation 2. Polarity within the cell 3. Extracellular signaling

  3. Transcriptional Regulatory Cascades • Transcription proteins and cofactors – activators and repressors • Cis-acting elements • Locus arrangement (gene order) • Chromatin structure – domains, methylation, acetylation • Cell polarity and signal transduction

  4. Cis-acting transcriptional regulatory elements: Definitions Locus Control Region (LCR) 1.Opens locus chromatin domains 2.Insulates against effects of surrounding positive or negative chromatin 3.Has cell lineage-specific enhancer activity 4. Influences timing of replication and choice of origin utilized Enhancer 1.Stimulates transcription in an orientation-independent manner 2.Classical enhancers function independently of orientation and distance Promoter 1.Region of DNA at which RNA polymerase binds and initiates transcription Response elements 1.Causes a gene to respond to a regulatory transcription factor

  5. Cis-acting transcriptional regulatory elements: Definitions (continued) Insulator 1.Creates independent functional domain without enhancement or activation function by blocking effects of surrounding positive or negative chromatin 2.     Interrupts communication between a promoter and another regulatory element when placed between them Matrix attachment region (MAR) or scaffold attachment region (SAR) 1.DNA segment that may bind the nuclear scaffold 2.     A DNA loop between two MARs may form an independent chromosomal domain 3.     Has no enhancer activity

  6. Insulator Insulator LCR HS HSs HS Promoters Enhancers Response elements (Regulatory promoter) MAR MAR

  7. Action of trans-acting transcription factors Transcriptional environment is dynamic and changes as development proceeds.

  8. Control of human b-globin gene expression – a model of developmental transcription regulation a-globin • Carries O2 and CO2 • Tetramer (a2b2) • Allosteric regulation • Tetramer composition varies with age b-globin

  9. Synthesis of hemoglobin is coordinately regulated

  10. Pattern of globin chain synthesis during development

  11. HS-40 LCR • The human globin genes • Each gene cluster is under the control of • a major enhancer (HS –40) or locus control region (LCR) a b a b a-like genes on chr 16 z a2 a1 b-like genes on chr 11 e Gg Ag d b

  12. b-globin chain

  13. The Locus Control Region • The LCR is DNAse-hypersensitive in cells expressing the globin genes • Sensitivity to DNAse reflects a relaxed chromatin structure that allows • binding of transcription factors • The LCR regulates the entire gene cluster permitting it to be further • regulated on a gene-by-gene basis +1 promoter transcribed region LCR DNAse- hypersensitive sites Sites that are less-sensitive to DNAse between nucleosomes and at other regulatory regions adjacent to genes

  14. The LCR and the globin genes bind common protein factors

  15. Prototypicalb-like globin gene Promoter Enhancer

  16. Models proposed for LCR-globin gene interaction A) Looping B) Tracking

  17. C) Facilitated tracking D) Linking

  18. Cellular Polarity • Morphogen gradient A morphogen is a protein whose local concentration (or activity) causes the surrounding region to take up a particular structure or fate. • Patterning Partitioning of the cell or embryo into “zones” destined to develop into different tissues or structures.

  19. A series of events resulting from the initial asymmetry within the egg is translated into the control of gene expression so that specific regions of the egg acquire different properties. (top) Anterior (head) Posterior (tail) (underneath) At the start of development, gradients are established in the egg along two axes, anterior-posterior and dorsal-ventral.

  20. Regulatory cascades - concept

  21. Maternal gene products, called morphogens, establish gradients in early embryogenesis. • Anterior-posterior development uses localized gene regulators. • Dorsal-ventral development uses localized receptor-ligand interactions.

  22. Expressed during oogenesis by the mother. Act upon or within the maturing oocyte. Expressed after fertilization. Mutations in these genes alter the number or polarity of segments. Three groups of segmentation genes act sequentially to define increasingly smaller regions of the embryo. Control the identity of a segment, but do not affect the number, polarity or size of segments. Mutations in these genes cause one body part to develop the phenotype of another part.

  23. Homeotic (Hox) Genes Lab pb Zen Dfd Scr Antp Abd-A Abd-B Ubx • Impose the program that determines the unique differentiation of each segment. • Complex loci found as gene clusters. 3. Spatial colinearity – Hox gene order strictly corresponds to their expression domains along the body of the embryo.

  24. Hox gene clusters are conserved between species. Drosophila Chromosome pb Dfd Antp Abd-A Abd-B lab Scr Ubx BX-C ANT-C 3 Mouse A1 A2 A3 A4 A5 A6 A7 A9 A10 A11 Evx1 A13 HoxA 6 B1 B2 B3 B4 B5 B6 B7 B8 B9 B13 HoxB 11 C4 C5 C6 C8 C9 C10 C11 C12 C13 HoxC 15 D1 D3 D4 D8 D9 D10 D11 D12 D13 Evx2 2 HoxD anterior 3’ 5’ posterior Human and Mouse: Four gene clusters (A, B, C, D) that are organized into 13 paralogue groups.

  25. B1 B2 B3 B4 B5 B6 B7 B8 B9 B13 Spatial colinearity in mouse Adapted from Hunt et al. (1991) Development Supp.: 187-197.

  26. Comparison of spatial colinearity between fruit fly and mouse. Humans have the same number of Hox gene clusters as mice and spatial colinearity is conserved between species.

  27. Combinations of Hox genes specify the development of the anterior-posterior axis

  28. 1 2 3 4 5 6 7 9 10 11 13 earliest latest direction of opening of chromatin in complex during gastrulation anterior 3’ 5’ posterior Temporal colinearity in mouse Temporal colinearity: As the body plan develops in an anterior-posterior direction during gastrulation, there is a sequential expression of the homeotic complex.

  29. Diseases associated with Hox gene mutations • Hand-foot-genital syndrome (Hoxa deletion) • Synpolydactyly (Hoxd deletion) • Cleft palate • Brain abnormalities • Uterine abnormalities • Retinoic acid, which causes birth defects, affects Hox genes Polydactyly

  30. Extracellular Signaling • Communication of environmental stimuli to intracellular milieu, thus effecting appropriate cellular (developmental) response • Four types • Endocrine • Paracrine • Neuronal • Contact-dependent

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