Distinct Mammalian Precursors Are Committed to Generate Neurons with Defined Dendritic Projection Patterns

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Abstract
The mechanisms that regulate how dendrites target different neurons to establish connections with specific cell types remain largely unknown. In particular, the formation of cell-type–specific connectivity during postnatal neurogenesis could be either determined by the local environment of the mature neuronal circuit or by cell-autonomous properties of the immature neurons, already determined by their precursors. Using retroviral fate mapping, we studied the lamina-specific dendritic targeting of one neuronal type as defined by its morphology and intrinsic somatic electrical properties in neonatal and adult neurogenesis. Fate mapping revealed the existence of two separate populations of neuronal precursors that gave rise to the same neuronal type with two distinct patterns of dendritic targeting—innervating either a deep or superficial lamina, where they connect to different types of principal neurons. Furthermore, heterochronic and heterotopic transplantation demonstrated that these precursors were largely restricted to generate neurons with a predetermined pattern of dendritic targeting that was independent of the host environment. Our results demonstrate that, at least in the neonatal and adult mammalian brain, the pattern of dendritic targeting of a given neuron is a cell-autonomous property of their precursors. The mammalian brain contains a large number of different classes of neurons that are connected in a specific manner. A long-standing question is how such stereotyped connections emerge during the assembly of the brain. Here, we investigated whether neonatal and adult brain stem cells give rise to neurons whose connections can be influenced by the partners that they encounter while maturing, or alternatively, whether these connections are predetermined from the moment that a neuron is born. We observed the existence of distinct populations of precursor cells committed to generating neurons with a specific pattern of connections. Furthermore, the pattern of connections formed by these neurons was largely independent of the environment in which the neurons matured. These results have important implications for the formation of neuronal circuits, as they indicate that the connections of a new neuron can be determined in their precursors. In particular, these observations suggest that for neuronal replacement therapies to be successful, it will be necessary to understand the genetic programs that control how stem cells are prespecified to produce neurons with a stereotypic pattern of connections.