Control of neurogenic vs astrogliogenic fate in a restricted spinal cord progenitor domain

MICAELA SARTORETTI; DI BELLA, DANIELA; CARCAGNO, ABEL; LANUZA, GUILLERMO

Sidney

Conferencia; Understanding the Function of Glia in the Healthy and Diseased CNS; 2015

University of Sydney

Despite of the high heterogeneity in morphology and function of astrocytes in central nervous system, there is still an incomplete understanding about the cellular and molecular control of their development. By using mouse genetics, we studied a small group of ventral progenitors of the embryonic spinal cord -called p0-, which expresses the transcription factor Dbx1. After the production of V0 Interneurons (V0-IN), this progenitor pool is later committed to generate a subset of astrocytes. We named it as vA0. Their precursors radially migrate to populate a defined region of the lateral spinal cord. Mosaic fluorescent labelling showed that vA0 population is composed by both protoplasmic and fibrous astrocytes, demonstrating that a single progenitor domain produces astrocytes with different morphological features. We found that Dbx1 controls specification of these astrocytes, as in its absence vA0 is augmented at the expense of V0-INs. Notch signalling plays key roles in binary fate-cell decisions and glial determination. We evaluated if this pathway modulates early decision between producing V0 neurons and vA0 astrocytes, and whether differential Notch activity could be involved in Dbx1 function. Presenilin1 mutants, that have severely attenuated Notch signalling, exhibited diminished p0-derived glial cells, while V0-INs numbers were increased. Impairing Notch pathway with Ly411575 only at neurogenic stages, but not later, showed similar results. Additionally, gliogenic precursors are increased in Dbx1 mutants and are reduced in Psen1 mutants after the neurogenic stage. This prompted us to analyze key players of Notch signalling pathways in Dbx1 wt and mutant neural tubes before the initiation of gliogenesis. Surprisingly, while wild type p0 domain expresses Delta1 ligand, this domain is converted into Jagged1 positive in the absence of Dbx1. Our results suggest that the type of Notch ligand directed by Dbx1 transcription factor controls the differentiation of p0 precursors by biasing neurogenic vs astrogliogenic fate.