The ability of the nervous system to integrate complex sensory information and produce well-controlled behaviors relies on the precise assembly of neuronal networks during development. The goal of this collaborative project is to examine two key aspects of circuit assembly: The first aspect is the topographic organization of neuronal projections that connect specific parts of one brain area with a second area. This property of neuronal circuits ensures that positional information of sensory inputs is maintained and can be integrated. We will focus specifically on two major afferent systems in the mouse brainstem and their unique synapses: Calyx of Held synapses formed by globular bushy cells in the medial nucleus of the trapezoid body (MNTB) and cerebellar mossy fiber synapses formed by pontine afferents in the cerebellum. The second aspect is the elaboration of specialized synaptic structures. Synapses are the key processing units that tie individual neurons into networks. The functional properties of individual synapses have important impact on the transduction of neuronal information, e.g. synaptic properties determine whether signals are amplified with repetitive stimulation, whether small stimuli elicit responses in a synaptic partner or, alternatively, whether only strong accumulating stimulation leads to activation of the synaptic partner cell. The key hypothesis addressed in this proposal is that transcriptional programs in neuronal cells provide a code for the topography and specificity of synaptic partner choice and for the differentiation of specialized presynaptic structures. We will examine the role of transcription factors in specifying spatially restricted neuronal populations with specific projection patterns, the role of target-derived signals that drive the elaboration of the structurally and functionally highly specialized presynaptic structures. The collaborative approach will allow us to integrate data from the two model systems (cerebellar mossy fiber synapses and calyx of Held synapses) to define conceptual similarities but also to provide insights into context-specific (divergent) roles of molecular mechanisms for neuronal wiring. The three investigators participating in this project each provide unique and specialized forms of expertise that are required for jointly achieving the goals of this project. This expertise includes: (1) insight into the anatomical fine structure of the brainstem, (2) advanced mouse genetic techniques, (3) expertise in electrophysiological studies on synaptic function, (4) cell biological approaches to obtain a mechanistical understanding of synaptic specificity.