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

Int J Dev Biol. 2010;54(10):1453-64. doi: 10.1387/ijdb.093041ki.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Calcium-Binding Proteins / genetics
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Jagged-1 Protein
  • Jagged-2 Protein
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis*
  • Olfactory Mucosa / embryology*
  • Olfactory Mucosa / growth & development
  • Olfactory Mucosa / metabolism
  • Olfactory Receptor Neurons / cytology*
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Receptor, Notch2 / genetics
  • Receptor, Notch2 / metabolism
  • Serrate-Jagged Proteins
  • Stem Cells / cytology
  • Stem Cells / physiology*

Substances

  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Calcium-Binding Proteins
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • Jag1 protein, mouse
  • Jag2 protein, mouse
  • Jagged-1 Protein
  • Jagged-2 Protein
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Notch1 protein, mouse
  • Notch2 protein, mouse
  • Receptor, Notch1
  • Receptor, Notch2
  • Serrate-Jagged Proteins
  • Six1 protein, mouse
  • NeuroD protein
  • Neurog1 protein, mouse