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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.