Differentiation the step ahead of higher organisms Cockburn

Differentiation: the step ahead of higher organisms

Cockburn and Rossant, 2010

Parisi et al. , 2008

wt Klf 5 -/- Parisi et al. , 2013

Cdx 2 GATA 3 Eomes Oct 4 Sox 2 Nanog

YAP Gata 3 Cdx 2 Ralston et al. , 2010 merge Cdx 2 Morula Cdx 2 Blastocyst Nishioka et al. , 2009 Gata 3 ? 16 Ramos & Camargo, 1012 30

Pluripotency

ES All cell types

BMP 4 mouse ESCs BMP 4 Epi. SCs TFs neu-ecto p. TFs mes-endo p. LIF Nodal BMP 4 TFs

Self-renewal

ES All cell types

Le caratteristiche di una cellula sono definite dal programma di funzionamento dei suoi geni On/Off Sequence-specific DNA binding factors + Co-regolatori Fattori di rimodellamento della cromatina Enzimi che modificano gli istoni Enzimi che modificano i fattori trascrizionali … Decine di migliaia di geni

ESCs i. PS Ethical issue Government restrictions Tumor formation Chromosomal stability Rejection

ESCs i. PS Transdifferentiated cells Neural stem cells Mesenchymal stem cells

Parkinson Huntington SLA SCI Stroke Diabetes Myocardial infarction Hepatic failure …

Darwin’s theory Natural variations among individuals may improve the chances of survival and reproduction. Individuals performing better than other are positively selected and transmit this characteristic to the progeny Molecular evolution Genetic information undergoes spontaneous mutations. Most of them are silent or lethal. Some of them could confer an advantage that, of course, is transmitted to the progeny.

A coupled replication-translation system REPLICATION NEW GENES MUTATIONS TRANSLATION NEW PROTEINS NEW FUNCTIONS NEW SPECIES

Selective pressure (Darwin) Primitive ribosome Primitive t. RNAs Primitive m. RNA encoding a replicase

Let’s consider that there are 1022 stars and that every 10 th star has a habitable planet, hence 1021 habitable planets Each planet is of the size of earth and has a 10 kilometer (106 cm) thick habitable layer; the volume of the habitable layer is 4/3π[R 3 -(R-l)3] ≈ 5 × 1024 cm 3 (1% of this layer possesses the right conditions) The rate of the synthesis of RNA molecules of size n is 1 molecule/cm 3/second The time available after the Big Bang is 1010 years ≈ 3 × 1017 seconds Then, the number of unique RNAs n-mers "tried out" during the time after the Big Bang is: S ≈ 5 × 1022 × 1021 × 3 × 1017 ≈ 1. 5 × 1061

Let us assume that, for the onset of biological evolution, a unique RNA of size n is required. The number of such sequences is N = 4 n ≈10 0. 6 n. Then, the expectation of the number of times a unique n-mer emerges in the considered region is: E = S/N = 1. 5 × 1061/10 0. 6 n and n = log (E × 1. 5 × 1061)/0. 6. Substituting E = 1, we get n ≈100 nucleotide.

The requirements for the emergence of a primitive, coupled replicationtranslation system, which could trigger a Darwinian selection process are, at a minimum: - two r. RNAs with a total size of at least 1000 nucleotides - ~10 primitive t. RNAs of ~30 nucleotides each, in total, ~300 nucleotides - at least one RNA encoding a replicase, ~500 nucleotides. In the above notation, n = 1800, resulting in E -1018 <10

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