Six1 is indispensable for production of functional progenitor cells during olfactory epithelial development

Abstract

The rodent olfactory epithelium (OE) is a good model system for studying the principles of stem and progenitor cell biology, because of its capacity for continuous neurogenesis throughout life and relatively well-characterized neuronal lineage. The development of mouse OE is divided into two stages, early and established neurogenesis. In established neurogenesis, which starts at embryonic day (E) 12.5, sustentacular cells and olfactory receptor neurons (ORNs) are produced from apical and basal progenitors, respectively. We previously reported that Six1 -/-shows a lack of mature ORNs throughout development and disorganization of OE after E12.5. However, the molecular bases for these defects have not been addressed. Here, we show that Six1 is expressed in both apical and basal progenitors. In Six1 -/-mice, apical proliferating cells were absent and no morphologically identifiable sustentacular cells were observed. Consistently, the expression of Notch2 and Jagged1 in the apical layer was absent in Six1 -/-mice. On the other hand, basal proliferating cells were observed in Six1 -/-animals, but the expression of Ngn1, NeuroD, Notch1, and Jagged2 in the basal layer was absent. The expression of Mash1, the determination gene for ORNs, and Hes genes was enhanced in Six1 -/-mice. The present findings suggest that Six1 regulates production of functional apical and basal progenitors during OE development, through the regulation of various genes, such as neuronal basic helix-loop-helix (bHLH), neuronal repressor bHLH, and genes involved in the Notch signaling pathway.

Six1 expression is associated with a poor prognosis in patients with glioma

“…processes, such as proliferation, apoptosis, migration, and invasion (9,(21)(22)(23). The Six1 homeoprotein is a member of the Six family of homeodomain transcription factors and has been found to be upregulated in multiple cancers, including breast cancer (12,20,24), rhabdomyosarcomas (18,25,26), hepatocellular carcinomas (19), ovarian cancer (13) and Wilms' tumors (17).…”

A lifetime of neurogenesis in the olfactory system

“…In the murine OE, the first signs of cellular differentiation can be observed at embryonic day 10 (E10), when the epithelium already contains dark (embryonic stem cells; Pax7+; Murdoch et al, 2010) and pale (developing sensory neurons) cells. At this stage, the proliferation of progenitor cells is dependent upon retinoic acid and Six1 (Ikeda et al, 2010; Paschaki et al, 2013). However, the hallmark layering of the epithelium is not visible until later in development (E13–E15).…”

SIX1 is overexpressed in endometrial carcinoma and promotes the malignant behavior of cancer cells through ERK and AKT signaling

“…SIX1 expression level is increased in embryogenesis and promotes progenitor cell expansion and survival (6)(7)(8). SIX1 absence results in the reduction in size or loss of numerous organs, as a result of inhibited proliferation and increased apoptosis in mice (9).…”