Deciphering the conserved dynamic transcriptional signature and regulatory software governing neuronal fate commitment

The transcriptional program underlying neuronal apoptosis and survival has to date been partially characterized. However, the complete spectrum of genes/proteins as well as the ‘regulatory software’ controlling neuronal fate decisions remain almost entirely unknown. Here, for the first time, we characterized the earliest molecular events following the induction of neuronal apoptosis and its rescue by three potent anti-apoptotic growth factors (GFs), in order to identify key genes and upstream regulators primarily responsible for driving execution of these processes. A core set of 175 survival-related genes (SRGs) with opposite transcriptional signatures between apoptosis and GF-mediated survival was identified. Promoter motif analysis of SRGs revealed a repertoire of intrinsic upstream regulators that may drive the apoptotic/survival switch, with Hoxd9 predicted to be the master regulator. Finally, the clinical implication of SRGs in the pathogenesis of neurological and neuropsychiatric diseases, here emerged, suggested their potential utility as targets for treating these severe disorders. Time-course transcriptional analysis of serum-deprived cerebellar granule neurons (CGNs) after 0.5h, 1h and 3h switch from 25 mM (K25) to 5 mM KCl (K5), in the presence or absence of a maximal effective dose of SP (200 nM), Pacap (100 nM) or Igf1 (3.26 pM). Four biological replicates (derived from the same litter) for each experimental condition (K25, K5, K5+SP, K5+Pacap, K5+Igf1) were analyzed.