The making of an organ: RNA mediated developmental controls in mice

Based initially on the observation of inheritance patterns at variance with Mendel's first law, hereditary epigenetic variations were evidenced in the mouse. Modulating the transcription of a locus, they are induced by RNAs with sequence homology to the transcript. RNAs transferred by the gamete, including sperm, to the fertilized egg appeared to be responsible for transgenerational maintenance of the variant phenotypes. Instances of RNA-dependent variations so far analyzed in the mouse-a pathological deviation of heart development and a syndrome of gigantism initiated by hyperproliferation of embryonic stem cells-suggest a general dependence of organogenesis on epigenetic controls of gene expression. "I conclude it is impossible to say we know the limit of variation."-Charles Darwin. One of the most fascinating visions offered to the biologist is to watch the fertilized egg ingeniously unfolding a program to create a novel being. Development takes place by activating networks of gene activation that result in the proper adjustment of cell growth and functional differentiation. How is the whole process started? Thoughts are generally centered on the activation of critical genes at the early stages due to a newly acquired organization of their chromatin structures. Is the embryo induced to start a given program by molecules contributed by the maternal and paternal gametes? While genetic determinants are clearly essential, the epigenetic landscape largely dominates our current way of thinking. In this essay, we will focus on the evidence showing that RNA molecules are present in the gametes and that RNA can modulate the robust genetic program of organ formation in the mouse.