Initiation of olfactory placode development and neurogenesis is blocked in mice lacking both Six1 and Six4

Abstract

Mouse olfactory epithelium (OE) originates from ectodermally derived placode, the olfactory placode that arises at the anterior end of the neural plate. Tissue grafting and recombination experiments suggest that the placode is derived from a common preplacodal domain around the neural plate and its development is directed by signals arising from the underlying mesoderm and adjacent neuroectoderm. In mice, loss of Six1 affects OE morphogenesis but not placode formation. We show here that embryos lacking both Six1 and Six4 failed to form the olfactory placode but the preplacodal region appeared to be specified as judged by the expression of Eya2, which marks the common preplacodal domain, suggesting a synergistic requirement of Six1 and Six4 in patterning the preplacodal ectoderm to a morphologic placode. Our results show that Six1 and Six4 are coexpressed in the preplacodal ectoderm from E8.0. In the olfactory pit, Six4 expression was observed in the peripheral precursors that overlap with Mash1-expressing cells, the early committed neuronal lineage. In contrast, Six1 is highly distributed in the peripheral regions where stem cells reside at E10.5 and it overlaps with Sox2 expression. Both genes are expressed in the basal and apical neuronal progenitors in the OE. Analyses of Six1;Six4 double mutant embryos demonstrated that the slightly thickened epithelium observed in the mutant was not induced for neuronal development. In contrast, in Six1(-/-) embryos, all neuronal lineage markers were initially expressed but the pattern of their expression was altered. Although very few, the pioneer neurons were initially present in the Six1 mutant OE. However, neurogenesis ceased by E12.5 due to markedly increased cell apoptosis and reduced proliferation, thus defining the cellular defects occurring in Six1(-/-) OE that have not been previously observed. Our findings demonstrate that Six1/4 function at the top of early events controlling olfactory placode formation and neuronal development. Our analyses show that the threshold of Six1/4 may be crucial for the expression of olfactory specific genes and that Six1 and Six4 may act synergistically to mediate olfactory placode specification and patterning through Fgf and Bmp signaling pathways.

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). However, SIX1 expression is low in adult tissues, and aberrant expression of the SIX1 gene in adult tissue may contribute to carcinogenesis (10).…”

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

“…Six1 encodes a transcription factor and plays critical roles in the development of sensory organs (Zheng et al, 2003;Ozaki et al, 2004;Ikeda et al, 2007;Chen et al, 2009). We reported previously that Six1 is expressed in the OP and developing OE of mouse.…”

SIX1 acts synergistically with TBX18 in mediating ureteral smooth muscle formation

“…As we have previously found that loss of Six1 leads to abnormal cell death in the otic vesicle, the olfactory epithelium and in the pharyngeal endoderm-derived organs Zou et al, 2006;Chen et al, 2009), it is possible that a subpopulation of the…”

“…Since the mutant mice contain a lacZ gene driven by the Six1 promoter, and the inserted lacZ transgene displayed a pattern identical to the Six1 mRNA distribution obtained by in situ hybridization (Chen et al, 2009;Laclef et al, 2003;Xu et al, 2003;Zheng et al, 2003), we stained for b-galactosidase activity in Six1 lacZ heterozygotes. Six1 expression was observed in the ureteral mesenchyme from ~E12.5 (Fig.…”