Human and mouse are different and understanding of such differences is vital for modeling human diseases on mouse.We previously documented a self-enforcing regulatory loop consisting of an RNA binding protein (PTB), a microRNA (miR-124), and a transcription repressor complex (REST), which is necessary and sufficient to induce functional neurons from mouse fibroblasts.Unexpectedly, activation of this loop only induced immature neurons from human fibroblasts.We now uncovered a second loop comprising the PTB paralog (nPTB), another microRNA (miR-9), and a key transcription activator (Brn2), which is automatically triggered in mice but has to be separately activated in humans to promote neuronal maturation.We further showed that nPTB binds antisense nascent transcripts to gauge the transcription bubble critical for sense transcription from the Brn2 promoter, thus unveiling the functional significance of divergent transcription in mammalian genomes.Together, these findings suggest two separate gatekeepers for neuronal induction and maturation in humans.