Two major mechanisms regulating cell-fate decisions in the developing nervous system

Abstract

Two types of determinants appear to be responsible for the generation of neural cell diversity: non-cell-autonomous and cell-autonomous cues. We have identified both types of determinants through the intensive screening of P-element induced Drosophila mutants affected in neural development. As a member of the first category argos (also referred to as strawberry or giant lens), which regulates cell-cell interaction in the developing nervous system, needs to be mentioned. On the basis of the phenotype on loss of function of argos. its expression pattern and the predicted structure of its product (a secreted protein with a putative epidermal growth factor (EGF) motif) we propose that argos encodes a diffusible protein with pleiotropic functions that acts as a signal involved in lateral inhibition within the developing nervous system and also as a factor involved in axonal guidance. As a member of the second category, I refer to the Drosophila musashi gene that is required for lineage formation and asymmetric division of precursor cells in the developing nervous system. The musashi gene encodes a neural RNA-biding protein and is thus likely to regulate the asymmetric cell division of neural precursor cells by controlling the expression of target genes at the post-transcriptional level. We have identified its mammalian homologue, mouse-musashi-1 (m-Msi-1). In the developing central nervous system (CNS), m-Msi-1 expression was highly enriched to neural precursor cells as is the expression of nestin. Based on the results of a single cell culture experiment, m-Msi-1 expression appears to be associated with multipotent cells that are capable of self-renewal and with the generation of committed precursor cells of both neurons and glia. However, fully differentiated neuronal and glial cells lost their m-Msi-1 expression. The expression of m-Msi protein showed a complementary pattern to that of another mammalian RNA-binding protein Hu, which is localized in differentiated neurons in the CNS. Based on such differential expression patterns and its similarity to the Drosophila musashi, we propose that a combination of neural RNA-binding proteins are required for the asymmetric distribution of intrinsic determinants in the developing mammalian nervous system. The Drosophila glial-specific homeobox protein, Repo, can also be classified as a cell-autonomous cue regulating cell-fate decision during neural development. Repo expression is required for terminal differentiation and for the survival of glial cells.

Keywords: argos; asymmetric cell division; cell fate decision; cell-autonomous; cell-cell interaction; musashi; repo.