SummaryA fundamental question in developmental neuroscience is how a collection of progenitor cells proliferates and differentiates to create a brain of the appropriate size and cellular composition. To address this issue, we devised lineage-tracing assays in developing zebrafish embryos to reconstruct entire retinal lineage progressions in vivo and thereby provide a complete quantitative map of the generation of a vertebrate CNS tissue from individual progenitors. These lineage data are consistent with a simple model in which the retina is derived from a set of equipotent retinal progenitor cells (RPCs) that are subject to stochastic factors controlling lineage progression. Clone formation in mutant embryos reveals that the transcription factor Ath5 acts as a molecular link between fate choice and mode of cell division, giving insight into the elusive molecular mechanisms of histogenesis, the conserved temporal order by which neurons of different types exit the cell cycle.

Sound perception relies on the planar polarization of the mechanosensory hair cell apex, which develops a V-shaped stereocilia bundle pointing toward an eccentric kinocilium. It remains unknown how intrinsically asymmetric bundles arise and are concomitantly oriented in the tissue. We report here that mInsc, LGN, and Gαi proteins, which classically regulate mitotic spindle orientation, are polarized in a lateral microvilli-free region, or "bare zone," at the apical hair cell surface. By creating and extending the bare zone, these proteins trigger a relocalization of the eccentric kinocilium midway toward the cell center. aPKC is restrained medially by mInsc/LGN/Gαi, resulting in compartmentalization of the apical surface that imparts the V-shaped distribution of stereocilia and brings the asymmetric bundle in register with the relocalized kinocilium. Gαi is additionally required for lateral orientation of cochlear hair cells, providing a possible mechanism to couple the emergence of asymmetric stereocilia bundles with planar cell polarity.

In the developing mouse retina, multipotent retinal progenitor cells (RPCs) give rise to specific retinal cell types at different times, but the molecular mechanisms regulating how RPCs change over time remain unclear. In the Drosophila neuroblast lineage, the zinc finger transcription factor Hunchback (Hb) is both necessary and sufficient to specify early-born neuronal identity. We show here that Ikaros, a mouse ortholog of Hb, is expressed in all early embryonic RPCs, which then give rise to Ikaros-negative RPCs at later stages in the lineage. Remarkably, misexpression of Ikaros in late RPCs is sufficient to confer competence to generate early-born neurons. Conversely, Ikaros mutant mice have reduced numbers of early-born cell types, whereas late-born cell types are not affected. These results suggest a model in which Ikaros expression is both necessary and sufficient to confer early temporal competence to RPCs and raise the possibility that a similar strategy might be used to control the sequential order of cell birth in other parts of the nervous system.