Drosophila Neurotrophins Reveal a Common Mechanism for Nervous System Formation

Abstract

Neurotrophic interactions occur in Drosophila, but to date, no neurotrophic factor had been found. Neurotrophins are the main vertebrate secreted signalling molecules that link nervous system structure and function: they regulate neuronal survival, targeting, synaptic plasticity, memory and cognition. We have identified a neurotrophic factor in flies, Drosophila Neurotrophin (DNT1), structurally related to all known neurotrophins and highly conserved in insects. By investigating with genetics the consequences of removing DNT1 or adding it in excess, we show that DNT1 maintains neuronal survival, as more neurons die in DNT1 mutants and expression of DNT1 rescues naturally occurring cell death, and it enables targeting by motor neurons. We show that Spätzle and a further fly neurotrophin superfamily member, DNT2, also have neurotrophic functions in flies. Our findings imply that most likely a neurotrophin was present in the common ancestor of all bilateral organisms, giving rise to invertebrate and vertebrate neurotrophins through gene or whole-genome duplications. This work provides a missing link between aspects of neuronal function in flies and vertebrates, and it opens the opportunity to use Drosophila to investigate further aspects of neurotrophin function and to model related diseases.

Author Summary

Neurotrophins are secreted proteins that link nervous system structure and function in vertebrates. They regulate neuronal survival, thus adjusting cell populations, and connectivity, enabling the formation of neuronal circuits. They also regulate patterns of dendrites and axons, synaptic function, memory, learning, and cognition; and abnormal neurotrophin function underlies psychiatric disorders. Despite such relevance for nervous system structure and function, neurotrophins have been missing from invertebrates. We show here the identification and functional demonstration of a neurotrophin family in the fruit fly, Drosophila. Our findings imply that the neurotrophins may be present in all animals with a centralised nervous system (motor and sensory systems) or brain, supporting the notion of a common origin for the brain in evolution. This work bridges a void in the understanding of the Drosophila and human nervous systems, and it opens the opportunity to use the powerful fruit fly for neurotrophin related studies.

Abstract

Members of the neurotrophin superfamily mediate critical roles in neuronal survival and targeting in the fruit fly Drosophila. Although this is an accepted role for neurotrophins in vertebrates, scant previous evidence has been able to demonstrate such a conserved role in invertebrates.