The goal of the proposed project is to examine molecular mechanisms that regulate long-range neuroblast
migration and then dispersal within existing circuitry of the perinatal and postnatal forebrain. In human infants,
V-SVZ neurogenesis supplies neuroblasts to two long-range pathways, the rostral migratory stream (RMS) to
the olfactory bulb and the medial migratory stream (MMS) to the ventromedial prefrontal cortex (VMPC). The
MMS is unique to humans, but the RMS is found in most mammals. Studies of the mouse RMS reveal compact
‘chains’ of migratory neuroblasts surrounded by a dense meshwork of astrocytes. However, it is not clear which
signaling mechanisms establish and maintain controlled, large-scale and long-range tangential migration or the
distribution of new neurons to their target integration site. Eph-ephrin signaling is a common mechanism used in
development to coordinate axon guidance, cell migration, boundary discrimination and cell segregation through
adhesive and repulsive cell-cell interactions. During mouse postnatal development, RMS neuroblasts, which are
regionally specified with prescribed interneuron subclass fate, display differential Eph/ephrin expression profiles.
Absence of the most promiscuous of the Eph receptors, EphA4, results in severe disorganization of RMS
neuroblasts/astrocytes and aberrant neuroblast migration, with significantly fewer neuroblasts reaching the
periglomerular layer of the olfactory bulb. The heterogeneous expression of cell surface Ephs/ephrins by
neuroblasts is reminiscent of heterogeneous Eph/ephrin expression profiles that support topographical mapping
of retinotectal/thalamocortical axons.
The proposed experiments are designed to determine if Eph-ephrin networks are pre-determined in progenitor
subpopulations, contribute to the saltatory migration of neuroblasts and ultimately provide required cues for
topographical mapping within forebrain regions. In Aim 1, extensive single cell transcriptomic and proteomic
analyses will be used to identify progenitor subtypes and model higher order cell-cell interactions in the mouse
RMS. In Aim 2, single cell transcriptome and proteome analysis of Eph and ephrin expression will be used to
identify subpopulation distribution in the OB. In Aim 3, tissue clearing and immunolabeling techniques, together
with MR data, will allow 3D modeling of the human perinatal MMS and RMS, including cell-specific expression
of Ephs and ephrins (and activated forms). The R21 exploratory mechanism is used to initiate studies on long-
range neural progenitor migration pathways that persist after birth; the dysfunction of which may be linked to
neurodevelopmental disorders.