Ancestral regulatory mechanisms specify conserved midbrain circuitry in arthropods and vertebrates

Abstract

Corresponding attributes of neural development and function suggest arthropod and vertebrate brains may have an evolutionarily conserved organization. However, the underlying mechanisms have remained elusive. Here, we identify a gene regulatory and character identity network defining the deutocerebral–tritocerebral boundary (DTB) inDrosophila. This network comprises genes homologous to those directing midbrain-hindbrain boundary (MHB) formation in vertebrates and their closest chordate relatives. Genetic tracing reveals that the embryonic DTB gives rise to adult midbrain circuits that in flies control auditory and vestibular information processing and motor coordination, as do MHB-derived circuits in vertebrates. DTB-specific gene expression and function are directed bycis-regulatory elements of developmental control genes that include homologs of mammalianZinc finger of the cerebellumandPurkinje cell protein 4.DrosophilaDTB-specificcis-regulatory elements correspond to regulatory sequences of humanENGRAILED-2, PAX-2, andDACHSHUND-1that direct MHB-specific expression in the embryonic mouse brain. We show thatcis-regulatory elements and the gene networks they regulate direct the formation and function of midbrain circuits for balance and motor coordination in insects and mammals. Regulatory mechanisms mediating the genetic specification of cephalic neural circuits in arthropods correspond to those in chordates, thereby implying their origin before the divergence of deuterostomes and ecdysozoans.