Postnatal mouse subventricular zone neuronal precursors can migrate and differentiate within multiple levels of the developing neuraxis

The mammalian subventricular zone (SVZ) of the lateral wall of the forebrain ventricle retains a population of proliferating neuronal precursors throughout life. Neuronal precursors born in the postnatal and adult SVZ migrate to the olfactory bulb where they differentiate into interneurons. Here we tested the potential of mouse postnatal SVZ precursors in the environment of the embryonic brain: (i) a ubiquitous genetic marker, (ii) a neuron-specific transgene, and (iii) a lipophilic-dye were used to follow the fate of postnatal day 5–10 SVZ cells grafted into embryonic mouse brain ventricles at day 15 of gestation. Graft-derived cells were found at multiple levels of the neuraxis, including septum, thalamus, hypothalamus, and in large numbers in the midbrain inferior colliculus. We observed no integration into the cortex. Neuronal differentiation of graft derived cells was demonstrated by double-staining with neuron-specific β-tubulin antibodies, expression of the neuron-specific transgene, and the dendritic arbors revealed by the lipophilic dye. We conclude that postnatal SVZ cells can migrate through and differentiate into neurons within multiple embryonic brain regions other than the olfactory bulb.

Network of tangential pathways for neuronal migration in adult mammalian brain

Cells in the brains of adult mammals continue to proliferate in the subventricular zone (SVZ) throughout the lateral wall of the lateral ventricle. Here we show, using whole mount dissections of this wall from adult mice, that the SVZ is organized as an extensive network of chains of neuronal precursors. These chains are immunopositive to the polysialylated form of NCAM, a molecule present at sites of plasticity, and TuJ1, an early neuronal marker. The majority of the chains are oriented along the rostrocaudal axis and many join the rostral migratory stream that terminates in the olfactory bulb. Using focal microinjections of DiI and transplantation of SVZ cells carrying a neuron-specific reporter gene, we demonstrate that cells originating at different rostrocaudal levels of the SVZ migrate rostrally and reach the olfactory bulb where they differentiate into neurons. Our results reveal an extensive network of pathways for the tangential chain migration of neuronal precursors throughout the lateral wall of the lateral ventricle in the adult mammalian brain.

Adenovirus-mediated gene delivery into neuronal precursors of the adult mouse brain.

Precursor cells found in the subventricular zone (SVZ) of the adult brain can undergo cell division and migrate long distances before differentiating into mature neurons. We have investigated the possibility of introducing genes stably into this population of cells. Replication-defective adenoviruses were injected into the SVZ of the lateral ventricle of adult mice. The adenoviruses carried a cDNA for the LacZ reporter or the human p75 neurotrophin receptor, for which species-specific antibodies are available. Injection of the viruses into the SVZ led to efficient labeling of neuronal precursors. Two months after viral injection, infected cells were detected in the olfactory bulb, a significant distance from the site of injection. Labeled periglomerular and granular neurons with extensive dendritic arborization were found in the olfactory bulb. These results demonstrate that foreign genes can be efficiently introduced into neuronal precursor cells. Furthermore, adenovirus-directed infection can lead to long-term stable gene expression in progenitor cells found in the adult central nervous system.