Chapter 7 Retrotransposition and Neuronal Diversity Maria C. N. Marchetto, Fred H. Gage, and Alysson R. Muotri Contents 7.1 Introduction ................. 87 7.2 Silencing and Activation of L1 Retrotransposons 89 7.3 L1 Targets in Neuronal Progenitor Cells ............... 91 7.4 Environmental Regulation of L1 Activity in the Brain ................. 93 7.5 L1 Activity and Disease ........... 93 7.6 Evolutionary Consequences of L1 Impact in Neuronal Genomes ............ 94 References .................... 95 Abstract The generation of specialized cell types, such as neurons, derived from stem cells has been proposed as a groundbreaking technology for regener- ative medicine. Unfortunately, subtype-specific differ- entiation of functional neurons is extremely difficult. Understanding the mechanisms of neuronal diversi- fication is not only relevant for the proper differ- entiation of complex neuronal types but might also shed light on normal brain development and cognitive diversification. The recent finding that LINE-1 (Long Interspersed Nucleotide Elements-1, or L1) retroele- ments are active in somatic neuronal progenitor cells has provided a potential additional mechanism for gen- erating neuronal diversification. L1 retrotransposition in the nervous system challenges the idea of static neu- ronal genomes, adding a new element for neuronal A.R. Muotri () University of California at San Diego, School of Medicine, Department of Pediatrics/Rady Children’s Hospital San Diego and Department of Cellular and Molecular Medicine, La Jolla, CA 92093, MC 0695, USA e-mail: muotri@ucsd.edu plasticity. However, the extent of the impact of L1 on the neuronal genome is unknown. In this chapter we will discuss the potential influence of L1 retrotrans- position during brain development and the evolution- ary pressures that may have selected this unexpected machinery of diversity in neuronal precursor cells. Keywords Brain evolution · Genetic mosaicism · L1 retrotransposon · Neural stem cells · Selfish gene Abbreviations LINE-1 or L1 Long Interspersed Nucleotide Elements-1 NSC neural stem cell(s) EGFP enhanced green fluorescent protein EN endonuclease NRSE neuron-restrictive silencer element RT reverse transcriptase TPRT Target Primed Reverse Transcription UTR untranslated terminal repeats 7.1 Introduction It is known for more than a century, through the work of Camilo Golgi and Santiago Ramon y Cajal, that neurons are specialized cells with a huge diversity of shapes and connections. It is estimated that the human brain contains more than 10,000 different morpho- logical types of neurons. However, neuronal diversity cannot be defined only by morphology or anatomic position. Similar cells, located at the same brain region, may have distinct electrophysiological properties and unique connection within other neurons. Moreover, 87 H. Ulrich (ed.), Perspectives of Stem Cells, DOI 10.1007/978-90-481-3375-8_7, © Springer Science+Business Media B.V. 2010