TGF-betas mediate feedback regulation of neurogenesis and gliogenesis in the mammalian olfactory epithelium.

摘要

Proper tissue growth faces many obstacles: Considering genetic variability and environmental instability, how do developing tissues know when to stop growing or how many different cell types to produce? One strategy is to employ endogenous feedback signaling. A signal produced, by the differentiated cell types of a tissue, which feeds back to control the activity of proliferating stem and progenitor cells allows organs to tether their growth with the number of differentiated cell types in the system. This dissertation explains these ideas and discusses tissue culture, genetic and computational experiments used to understand the strategies that control developmental and regenerative neurogenesis in a model system, the olfactory epithelium (OE) of the mouse. Experiments presented here, in conjunction with previous work, show that neurogenesis and gliogenesis during OE development is regulated by multiple, stage-specific feedback loops. In the OE, neurons develop from a lineage consisting of two distinct precursor stages: a Sox2+/MASH1+ stem cell stage that gives rise to a Ngn1+ immediate neuronal precursor (INP) cell stage. Sox2+/MASH1+ stem cell proliferation is inhibited by ActivinbetaB, a TGF-beta produced endogenously by cells of the neuronal lineage; INP proliferation is inhibited by GDF11, an activin-like TGF-beta also produced endogenously within the OE. Mathematical modeling studies of unbranched cell lineages, in which Hill kinetics regulate proliferation, reveal that a feedback circuit consisting of ActivinbetaB and GDF11 can, in principle, simultaneously control cell number, cell-type ratios, and regenerative speed in this system. Phenotypic studies of Gdf11-/- mice, ActivinbetaB -/- mice, and mice null for both genes unexpectedly revealed that the stem cell of ORNs is also the progenitor of sustentacular cells, the intrinsic glial cells of the OE. These studies also show that ActivinbetaB and GDF11 exert opposite effects in regulating the fate choice of the OE stem cell (neuronal versus glial). These experiments support the hypothesis that tissue homeostasis is established, in part, by feedback signals that coordinate the rate at which stem and neuronal precursor cells divide with the number of end stage cells in the system.