Neurons in the subcallosal sling

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DESCRIPTION (provided by applicant): The glial sling was first described by Silver and colleagues in the early 1980's as a population of glioblast cells that arise in the medial aspect of the lateral ventricles. These cells migrate toward the midline during embryogenesis and form tight junctions, creating a sling-like structure that spans the two cerebral hemispheres. When the sling is severed the corpus callosum does not form; in congenitally acallosal mice or in marsupials (which lack a corpus callosum), there is no sling. These observations led to the hypothesis that the sling is required for the corpus callosum to form by guiding callosal axons across the midline. Surprisingly, we have recently discovered that the majority of glial sling cells label with neuronal rather than glial markers (see preliminary data). Preliminary electrophysiological experiments indicate that sling cells have excitable membranes and fire action potentials in response to long depolarizing pulses via whole-cell current clamp. Sling cells from postnatal animals display spontaneous action potentials that are reversibly blocked by TTX. Taken together, these new findings indicate that sling cells are neurons, not glia.Previous descriptive studies found that sling cells migrate from the medial subventricular zone to the midline between E15 and E17 in mice and that the sling disappears early postnatally. Once the sling cells reach the midline, it was proposed that they die and form a small cavity called the cavum septum pellucidum. However 11JNEL labeling shows that only a few cells undergo cell death at E17 and E18. Since the sling continues to be generated until P2 (see preliminary data) the absence of the sling by P5 may be due to additional (or other) mechanisms than cell death, such as cell migration away from the sling area. Preliminary experiments in organotypic slices and adenoviral labeling in vivo suggest that sling cells continue migrating past the midline to other areas of the brain. In aim 1 we extend these findings to determine where sling cells migrate in the developing brain. The sling is continuous with the SVZ of the cortex and may represent a previously unknown population of tangentially or contralaterally migrating cortical neurons. In aim 2 we investigate whether sling cells arise only at the cortico-septal boundary from a specialized sling progenitor population, or whether their progenitors are dispersed in more lateral regions of the SVZ. Using a recombinant retroviral library we determine whether sling cells are clonally related to cells of the cortical plate. Prenatally sling neurons are immature, in aim 3 we investigate their differentiation potential and determine if they are committed to a single, or to multiple, neuronal lineages. These experiments redefine the cellular makeup, migration and possible function(s) of the subcallosal sling during cortical development. Development of the sling is disrupted in a number of genetic acallosal mutants that display additional brain abnormalities. Neurons within the sling may function in the development of the brain and defects in their development may underlie some of these disorders