Figure 7. Schematic models of the ISC-EB feedback loop during normal homeostasis, regeneration and tumorigenesis.
(A) During normal homeostasis (left panel), ISC and EB typically exist as a progenitor pair. Sox21a is expressed in EB to promote EB differentiation and at the same time to restrict ISC activity by inhibiting paracrine signals, such as Spi, etc.. In Sox21a mutant midgut (right panel), continuous paracrine signals drives continuous activation of the ISC-EB loop, leading to massive production of differentiation-defective cells and tumorigenesis. (B) Sox21a-mediated amplification loop is employed in damage-induced intestinal regeneration. Tissue damage causes temporal downregulation of Sox21a in EB and consequently derepression of mitogenic factors, which act in a paracrine manner to promote ISC proliferation. This leads to a temporal activation of the ISC-EB amplification loop for rapid production of progenitor cells prepared for epithelial differentiation. During the recovery after the damage is withdrawn, Sox21a is temporally upregulated in EBs to promote epithelial differentiation and homeostasis reestablishment.