Brain evolution: Six anthropoid specific substitutions generate spatio-temporal expansion of reporter gene expression in the central nervous system of transgenic mice.

RODRIGO LÓPEZ-LEAL; GRETEL B. KAMM; MARCELO RUBINSTEIN; LUCÍA F. FRANCHINI

Congreso; Chilean Society for Cell Biology XXIV Annual Meeting; 2010

INTRODUCTION: The neocortex, the most prominent structural and functional innovation of the mammalian brain, has expanded independently in several mammalian lineages. In anthropoid primates this expansion reached a maximum composing around 80% of the entire brain mass. We hypothesize that uncovering the genetic basis of primate brain enlargement will help to understand human brain evolution. We identified an accelerated region that we have named DAANC, carrying 6 positively selected substitutions in the lineage leading to anthropoids upstream of Delta-like1 (DLL1), a gene involved in the proliferation/differentiation switch of neuronal precursors during brain development. METHODS: To study the ability of this region to act as a transcriptional enhancer we generated transgenic mice carrying the human (DAANC-Hs) and mouse (DAANC-Mm) ortholog regions and its mutated variants, upstream of the reporter gene lacZ. We studied comparatively the transcriptional activity of each region through lacZ expression between E9,5 and P1. RESULTS: We found that DAANC-Mm and DAANC-Hs act as developmental nervous system specific enhancers between E9.5 and E15.5. Swapping the six anthropoid-specific nucleotides into the mouse enhancer (DAANC-Mm*) expanded the spatio-temporal expression domain of lacZ in the developing neocortex between E14.5 to P1. Moreover, swapping the ancestral nucleotides back into the human ortholog (DAANC-Hs*) impaired enhancer function within the entire nervous system beyond E14.5. DISCUSSION: We propose that a spatio-temporal expansion of DLL1 expression driven by these six anthropoid-specific substitutions could have contributed to increase the number of neural precursors in the telencephalon and, ultimately, to shape a bigger brain.