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Metamorphosis Gradual - Incomplete Abrupt - Complete Gills to Lungs Tail to Legs Ammonia To Urea Herbivory Carnivory contralateral contralateral & ipsilateral Fig. 18.1, pg. 557 Chinese 3,000 B.C. identified thyroid disease Recommended seaweed, dessicated deer thyroids Iodide Thyroid Hormones Studies in 1912 linked thryoid gland to amphibian metamorphosis: - Tadpole metamorphosed early when given horse thyroid glands - Larvae do not metamorphose & become giant tadpoles without thyroid gland Hypothalamus & Pituitary Gland Hypothalamus Pituitary Gland Hypothalamic/Pituitary Vasculature LH FSH GH ACTH PRL TSH Posterior Anterior Preoptic nucleus Neural pathways PO Hypothalamus Neural endocrine pathway Median eminence ME Hypophysial portal Vasculature system/ Endocrine pathway Pituitary Thyroid stimulating hormone TSH Endocrine cells PRL Long-loop endocrine pathway Thyroid gland Prolactin T4 T3 TR-RXR RXR – retinoid receptor forms receptor dimer with TR’s TR-RXR is a transcriptional repressor T3-TR-RXR is a transcriptional activator TRalpha TRbeta – levels influenced by T3 Circulating T4 converted to T3 in cells PO ME TSH PRL - Thyroid is developing - T3/T4 low & rising - Pituitary developing - Hypothalamus undeveloped T3/T4 Premetamorphosis PO Limb tissues: High TRalpha High deiodinase II (T4 ME TSH Tail tissues: Low TRalpha No deiodinase II PRL ? + feedback for TSH secretion increasing T3/T4 + feedback for ME development Low T3 T3/T4 Early Prometamorphosis T 3) PO ME TRH Tail tissues: High TRbeta Expression of deiodinase II = tail resorption TSH PRL - completion of ME development & TRH secretion - increased TSH release T3/T4 - increasing T3/T4 Late Prometamorphosis PO ME TRH TSH -- PRL [TRbeta] peaks -T3/T4 Metamorphic Climax (TSH) TRs repress target transcription whereas, in the presence of T3, they enhance the transcription of these same genes TR/RXR heterodimers function as transcriptional repressors of T3-inducible genes in premetamorphic tadpoles to allow for animal growth and prevent premature metamorphosis and as transcriptional activators of these genes when T3 becomes available later to initiate metamorphic changes in different tissues. e.g. TRbeta (Schwind 1933) Differential & Temporal Tissue Sensitivity Fig. 18.5, pg. 561 Changes in Cardiovascular System Tadpole RBC’c replaced by Adult RBC’s (have different shape are are selectively digested by liver macrophages) Gene expression for hemoglobin proteins changed: - tadpole hemoglobins have higher binding capacity and slower ability to release O2 - adult hemoglobins have lower binding capacity and higher rate of O2 release 3 Groups of Thyroid Hormone Response Genes Transcription factors regulating other genes Cellular metabolism regulating genes Signaling genes – involved in regulating receptor pool for secreted molecules that provide ECM; proteases that act to cleave growth factors bound to ECM Tail Resoprtion: 35 genes upregulated / 10 downregulated Environment Light/Temp Facultative Neotene A. tigrinum Hypothalamus cold -- TRH hot + Pituitary -- TSH Thyroid -Necturus No receptors (+) A. mexicanum T3/T4 Obligate Neotene – Terrestrial form created Target Tissues Obligate Neotene – No terrestrial form What is the evolutionary significance of this response? Reduction in foraging occurs under these conditions; Reduction of food available to prometamorphic tadpoles in constant high water environment leads to accelerated metamorphosis Acceleration of metamorphosis: Developmental acceleration dependent upon rate of water reduction Not due to: Thermal differences Chemical changes Interaction between individuals Was reversible – deceleration of metamorphosis Hypothalamic corticotropin-releasing factor (CRF) neurons respond to environmental stressors, and CRF peptides stimulate the secretion of both thyroid hormone and corticosterone PO ME CRF TRH TSH -- ACTH -- PRL Adrenal Corticosterone T3/T4 Metamorphic Climax [TRbeta] peaks April 20, 2007 Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels Diabetes Genetics Initiative of Broad Institute of Harvard and MIT , Lund University and Novartis Institutes for BioMedical Research Richa Saxena 1, Benjamin F. Voight 2, Valeriya Lyssenko 3, Noel P. Burtt 4, Paul I.W. de Bakker 1, Hong Chen 5, Jeffrey J. Roix 5, Sekar Kathiresan 2, Joel N. Hirschhorn 6, Mark J. Daly 2, Thomas E. Hughes 5*, Leif Groop 7*, David Altshuler 1*, Peter Almgren 3, Jose C. Florez 1, Joanne Meyer 5, Kristin Ardlie 4, Kristina Bengtsson 8, Bo Isomaa 9, Guillaume Lettre 6, Ulf Lindblad 8, Helen N. Lyon 6, Olle Melander 3, Christopher Newton-Cheh 2, Peter Nilsson 3, Marju Orho-Melander 3, Lennart Råstam 8, Elizabeth K. Speliotes 10, Marja-Riitta Taskinen 11,Tiinamaija Tuomi 12, Candace Guiducci 4, Anna Berglund 3, Joyce Carlson 3, Lauren Gianniny 4, Rachel Hackett 4, Liselott Hall 3, Johan Holmkvist 3, Esa Laurila 3, Marketa Sjögren 3, Maria Sterner 3, Aarti Surti 4, Margareta Svensson 3, Malin Svensson 3, Ryan Tewhey 4, Brendan Blumenstiel 4, Melissa Parkin 4, Matthew DeFelice 4, Rachel Barry 4, Wendy Brodeur 4, Jody Camarata 4, Nancy Chia 4, Mary Fava 4, John Gibbons 4, Bob Handsaker 4, Claire Healy 4, Kieu Nguyen 4, Casey Gates 4, Carrie Sougnez 4, Diane Gage 4, Marcia Nizzari 4, Stacey B. Gabriel 4, Gung-Wei Chirn 5, Qicheng Ma 5, Hemang Parikh 3, Delwood Richardson 5, Darrell Ricke 5, Shaun Purcell 13 New strategies for prevention and treatment of type 2 diabetes require improved insight into disease etiology. We analyzed 386,731 common single nucleotide polymorphisms in 1,464 patients with T2D and 1,467 matched controls, each characterized for measures of glucose metabolism, lipids,obesity, and blood pressure. We identify and confirm three loci associated with T2D -- in a non-coding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 -- and replicate associations near HHEX and in SLC30A8 found by a recent whole genome association study. We identify and confirm association of a SNP in an intron of glucokinase regulatory protein with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues into the pathogenesis of common diseases.