Her9 controls the stemness properties of the hindbrain boundary cells

Abstract

Different spatiotemporal distribution of progenitor/neurogenic capacities permits that brain regions engage asynchronously in neurogenesis. In the hindbrain, rhombomere progenitor cells are the main contributors to neurons during the first neurogenic phase, whereas boundary cells participate later, relying on Notch3-activity. To analyze the mechanism(s) that maintain boundary cells as proliferative progenitors not engaging in neurogenesis, we addressed the role of the zebrafish Hes1 ortholog, Her9, in this cell population. her9 expression is temporarily sustained in boundary cells in a Notch-independent manner while they behave as non-neurogenic progenitors. Functional manipulations demonstrate that Her9 inhibits the onset of Notch-signaling and the neurogenic program, thus keeping boundary cells in the progenitor state. Combining multicolor clonal analysis with functional approaches, we reveal a role of Her9 in the expansion of boundary progenitors by promoting symmetric proliferative divisions and preventing neurogenic cell divisions. Moreover, Her9 regulates the proliferation of boundary cells by inhibiting the cell cycle gene cdkn1ca and potentially interplaying with CyclinD1. Altogether, Her9 maintains the stemness and proliferation of hindbrain boundary progenitors at early embryonic stages.