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Initiation of olfactory placode development and neurogenesis is blocked in mice lacking both Six1 and Six4
Binglai Chen1, Eun-Hee Kim, Pin-Xian Xu
1Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of NYU, New York, NY 10029, USA.
Insights
Six1 and Six4 proteins are crucial for forming the olfactory placode in mice. Their combined action is essential for early neuronal development and patterning in the olfactory epithelium.
Area of Science:
- Developmental Biology
- Genetics
- Neuroscience
Background:
- The olfactory epithelium (OE) in mice originates from the ectodermally derived olfactory placode.
- Placode development is influenced by signals from underlying mesoderm and adjacent neuroectoderm.
- Previous studies showed Six1 affects OE morphogenesis but not placode formation.
Purpose of the Study:
- To investigate the synergistic role of Six1 and Six4 in olfactory placode formation and neuronal development.
- To identify the specific cellular defects in OE development in the absence of Six1 and Six4.
- To elucidate the molecular pathways involving Six1 and Six4 in OE patterning.
Main Methods:
- Analysis of Six1;Six4 double mutant mouse embryos.
- Gene expression analysis (e.g., Eya2, Mash1, Sox2).
- Assessment of cell proliferation and apoptosis in the developing OE.
Main Results:
- Six1 and Six4 are coexpressed in the preplacodal ectoderm and olfactory pit.
- Embryos lacking both Six1 and Six4 failed to form the olfactory placode.
- Six1;Six4 double mutants showed defects in neuronal development, including increased apoptosis and reduced proliferation.
- Six1 deficiency led to altered neuronal lineage marker expression and cessation of neurogenesis.
Conclusions:
- Six1 and Six4 act synergistically and are essential for olfactory placode specification and patterning.
- These genes function at the top of early developmental events controlling OE formation and neuronal development.
- The threshold of Six1/4 activity is critical for olfactory-specific gene expression, potentially mediated by Fgf and Bmp signaling.
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.
