A transient decrease in mitochondrial activity is required to establish the ganglion cell fate in retina adapted for high acuity vision

Although the plan of the retina is well conserved in vertebrates, there are considerable variations in cell type diversity and number, as well as in the organization and properties of the tissue. The high ratios of retinal ganglion cells (RGCs) to cones in primate fovea and bird retinas favor neural circuits essential for high visual acuity and color vision. The role that cell metabolism could play in cell fate decision during embryonic development of the nervous system is still largely unknown. Here, we describe how subtle changes of mitochondrial activity along the pathway converting uncommitted progenitors into newborn RGCs increase the recruitment of RGC-fated progenitors. ATOH7, a proneural protein dedicated to the production of RGCs in vertebrates, activates transcription of the Hes5.3 gene in pre-committed progenitors. The HES5.3 protein, in turn, regulates a transient decrease in mitochondrial activity via the retinoic acid signaling pathway few hours before cell commitment. This metabolic shift lengthens the progression of the ultimate cell cycle and is a necessary step for upregulating Atoh7 and promoting RGC differentiation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/002998v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@60b51aorg.highwire.dtl.DTLVardef@111be27org.highwire.dtl.DTLVardef@1db19f8org.highwire.dtl.DTLVardef@1860da3_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG