Reelin Signaling Specifies the Molecular Identity of the Pyramidal Neuron Distal Dendritic Compartment

Abstract

SUMMARY The apical dendrites of many neurons contain proximal and distal compartments that receive synaptic inputs from different brain regions. These compartments also contain distinct complements of ion channels that enable the differential processing of their respective synaptic inputs, making them functionally distinct. At present, the molecular mechanisms that specify dendritic compartments are not well understood. Here, we report that the extracellular matrix protein Reelin, acting through its downstream, intracellular Dab1 and Src family tyrosine kinase signaling cascade, is essential for establishing and maintaining the molecular identity of the distal dendritic compartment of cortical pyramidal neurons. We find that Reelin signaling is required for the striking enrichment of HCN1 and GIRK1 channels in the distal tuft dendrites of both hippocampal CA1 and neocortical layer 5 pyramidal neurons, where the channels actively filter inputs targeted to these dendritic domains.

Neurobiology: Reelin Mediates Form and Function

“…Evolution is parsimonious and tends to adapt existing processes over and over again to meet multiple biological needs, such as neuronal migration and dendritic compartmentalization. The mechanisms described by Kupferman et al [6] may also extend to the developmental role of Reelin. Perhaps localized increases in tyrosine phosphorylation, triggered when a leading projection from a migrating cortical neuron encounters the preplate, results in redistribution of channels and receptors that recognize local positional cues instructing migrating neurons to disembark radial glia and enter the pre-plate.…”

“…The mechanisms responsible for establishment and maintenance of dendritic compartmentalization of ion channels are unknown. A recent study by Kupferman et al [6] elegantly explains that Reelin signaling, which is restricted to the distal dendrite, is responsible for localized enrichment of HCN1 channels. Reelin signaling controls neuronal positioning in the developing cerebral cortex, cerebellum, and hippocampus [7].…”

“…Floxed mice for Crk and CrkL provide a useful tool to test whether Reelin-dependent enrichment of ion channels is mediated by Crk and CrkL. In contrast to Reelin and Dab1, the levels of SFKs, Crk, and CrkL appear to be relatively similar in the proximal and distal dendrites [6,8]. Therefore, it is possible that while differential distribution of upstream proteins guides dendritic specification, uniformly distributed downstream proteins execute the specification based on localized increases in tyrosine phosphorylation.…”

“…Therefore, it is not easy to determine whether a particular phenotype arises as a direct consequence of the loss of Reelin signaling or whether it results as an indirect effect of aberrant development. To circumvent these complications, Kupfermann et al [6] utilized recombinant adeno-associated virus to deliver CRE recombinase to hippocampal neurons in newborn Dab1 floxed mice. This causes ablation of Dab1, a key signaling molecule which functions downstream of Reelin, and suppression of pathway activity without affecting development of the infected neurons.…”

“…Since Reelin signaling-dependent enrichment of HCN1 in the distal dendrite is also observed in layer V pyramidal neurons in the neocortex and CA1 pyramidal neurons in the adult hippocampus [6], this may represent a common and essential tool for dendritic specification throughout the postnatal life. Evolution is parsimonious and tends to adapt existing processes over and over again to meet multiple biological needs, such as neuronal migration and dendritic compartmentalization.…”