A Notch-mediated, temporal asymmetry in BMP pathway activation promotes photoreceptor subtype diversification

摘要

Neural progenitors produce neurons whose identities can vary as a function of the time that specification occurs. Here, we describe the heterochronic specification of two photoreceptor (PhR) subtypes in the zebrafish pineal gland. We find that accelerating PhR specification by impairing Notch signaling favors the early fate at the expense of the later fate. Using in vivo lineage tracing, we show that most pineal PhRs are born from a fate-restricted progenitor. Furthermore, sister cells derived from the division of PhR-restricted progenitors activate the bone morphogenetic protein (BMP) signaling pathway at different times after division, and this heterochrony requires Notch activity. Finally, we demonstrate that PhR identity is established as a function of when the BMP pathway is activated. We propose a novel model in which division of a progenitor with restricted potential generates sister cells with distinct identities via a temporal asymmetry in the activation of a signaling pathway. Author summary A major goal in the field of developmental neurobiology is to identify the mechanisms that underly the diversification of the subtypes of neurons that are needed for the function of the nervous system. When investigating these mechanisms, time is an often-overlooked variable. Here, we show that in the zebrafish pineal gland—a neuroendocrine organ containing mostly photoreceptors (PhRs) and projection neurons—different classes of PhRs appear in a temporal sequence. In this simple system, the decision to adopt a PhR fate is driven by the activation of the bone morphogenetic protein (BMP) signaling pathway. Following the final cell division of a PhR progenitor, the sister cells normally activate the BMP pathway at different times. When Notch signaling activity is abrogated, activation of the BMP pathway occurs earlier and synchronously, which in turn favors the development of early PhR fates at the expense of later fates. We propose a model in which preventing sister cells from activating a signaling pathway in a synchronous fashion after their final division allows diversification of cell fates.