4. GROWTH, REGENERATION, AGEING AND EVOLUTION GROWTH: the least well understood aspect of development FORM/PATTERN vs. GROWT/PROPORTION Intracellular mechanisms that drive cell growth are well understood but overall growth control remains largely mysterious. Cell multiplication Cell enlargement Growth by accretion O C) o V matrix o MYSTERIES: regulation of final size Why some stop growing while others grow indefinitely? Is final animal size limited by nutrient supply that is restricted by the amount of terminal capillaries which can not grow as fast as the volume of the 3D object? MORE MYSTERIES: control of relative proportions Why there are usually no overgrown parts? Soft tissues grow in proportion to the skeleton 66 TOTAL GROWTH T 50% cell proliferation 50% cell enlargement Pthrp-/- I í f Parathyroid hormone-related peptide (PTHrP) wt Pthrp receptor 'A Co// type X/n s/ŕu Sternal cartilage J, Pthrp-/- Periarticular chondrocytes Proliferating chondrocytes Prehypertrophic chondrocytes Hypertrophic chondrocytes Osteoblasts REGENERATION: Awakening of developmental pathways in adult organism. AGING AND SENESCENCE: decline of physiological functions with age, leading to decreased ability to cope with stresses and increased susceptibility to diseases. A part of developmental program or simply a result of wear and tear (drugs, alcohol, cigarets, woman)? SENESCENCE IS UNDER GENETIC CONTROL Longevity and time to attain reproductive maturity at puberty tor various mammals Maximum Ufa span (months) Length of gestation (months) Age at puberty (months) Man 1440 9 144 Finback whale m 12 — Indian elephant 840 21 156 Horse 744 11 12 Chimpanzee 534 8 120 Brown tear 442 7 72 Dog 4oe 2 7 Cattle 360 9 B Rhesus monkey 34a 5.5 36 Cat 336 2 15 Pig 324 4 4 Squirrel monkey 252 5 36 Sheep 240 5 7 Gray squirrel 1B0 1.5 12 European rabbit 156 1 12 Guinea-pig 90 2 2 House rat 56 0.7 2 Golden hamster 48 0,5 2 Mouse 43 0.7 1.5 Mutation accumulation or Selfish genes or Antagonistic pleiotrophy or Disposable soma? P. Medawar R. Dawkins G. Williams T. Kirkwood GENES CAN ALTER THE TIMING OF SENESCENCE INSULIN/IGF SIGNALING IN C. elegans AND Drosophila NEUROENDOCRINE REGULATION OF AGEING CELLULAR SENESCENCE: Irreversible growth arrest with no apoptosis. Cells are viable, functioning, but can not divide. ONA damage Chromatin instability Shgrt/dyshindional telomeres (replrcaliv& senescence) Stress signals (oxidative damage, culture shock) Oncogenes (oncogene-induced senescence) Irreversible arrest nl cell proliferation (senescence) ONCOGENE-INDUCED SENESCENCE AS A BARRIER TO TUMOR DEVELOPMENT normal cell + oncogene (rasV12) tumor apoptosis senescence Control K~rasV12 Normal tissue Adenoma pl6 P15 Dec! DcR2 Ki-67 Adenocarcinoma adenoma adenocarcinoma 03. ifí (C -o "vi o u m nj M "Q Ci 'y TO OJ u c Q? ■U tz v •Ľ 'r 'V adenoma adenocarcinoma ANTAGONISTIC PLEIOTROPY EVOLUTION AND DEVELOPMENT Nothing in biology makes sense unless viewed in the light of evolution Fish Sei In mender T( >r to i stí thick Hog Calf RüblMl Human 1. Ontogeny recapitulating the phylogeny: Haeckel 1869. 2. Neodarwinism: morphological changes appear gradually as a result of action of number of mutations each having a small effect. Changes arising from natural selection are called adaptive evolution or adaptation. 3. Most changes in DNA is not adaptive but neutral evolution, consisting of accumulation of mutations of no selective consequence that spread through the population from one generation to next (genetic drift). UNDERSTANDING OF DEVELOPMENT HELPS EVOLUTIONARY BIOLOGY TO ANSWER QUESTIONS THAT COULD NOT BE ANSWERED BEFORE BUT THE GENES REGULATING DEVELOPMENT OF ANALOGOUS STRUCTURES ARE THE SAME remaining Shh THE PRIMORDIAL ANIMAL Body plan genes - genes that specify the features common to all animals. Brachyury - expressed in differently shaped reagions in Xenopus, chick and mouse but they all correspond to what was previously a mesoderm. Thus the mesoderm is a real cell state definable by the expression of brachyury. THE PHYLOTYPIC STAGE: A stage in development at which all members of taxon show maximal morphological similarity. Among vertebrates, the phylotypic stage is the tailbud stage when all vertebrates have a dorsal nerve cord, segmented somites, ventral heart, and a set of pharyngeal arches. ZOOTYPE: Animal phyla = different body plans with no morhological homologies among them. Developmental biology now makes it possible to compare the expression patterns of key developmental genes between phyla. Some of theese seem to be conserved across the whole animal kingdom. They are active around the phylotypic stage for all the main animal groups examined. The totality of common expression domains is called the zootype. This cryptic anatomy of developmental gene expression patterns defines of what an animal actually is. WHAT REALLY HAPPENED IN EVOLUTION can be seen by comparing the expression pattern of key developmental genes that give rise to two different morphologies, one ancestral and one derived. Snakes, whales and flightless birds have lost limbs that their ancestors had. It is believed that the position of the limbs on the lateral plate is specified by the anteroposterior patterning systém of the whole body. This includes Hox genes but also the ParaHox and NK clusters. In the chick, Hoxc6 and Hoxc8 are expressed in the lateral plate between the two limb buds and repress limb formation in this region. In python that has no trace of forelimbs but a rudiment of hindlimbs, the Hoxc8 and 8 expression extends all the way to the head but stops just short of the rudimentary hindlimbs. Anterior Posterior