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A balance of BMP and notch activity regulates neurogenesis and olfactory nerve formation.

Maier E, Nord H, von Hofsten J, Gunhaga L - PLoS ONE (2011)

Bottom Line: Here, we provide evidence that both modulated Notch and bone morphogenetic protein (BMP) signaling affect the generation of neurons in the olfactory epithelium and reduce the number of migratory neurons, so called epithelioid cells.These data provide new insights into the early generation of neurons in the olfactory epithelium and the initial formation of the olfactory nerve tract.Our results present a novel mechanism in which BMP signals negatively affect Notch activity in a dominant manner in the olfactory epithelium, thereby regulating neurogenesis and explain why a balance of BMP and Notch activity is critical for the generation of neurons and proper development of the olfactory nerve.

View Article: PubMed Central - PubMed

Affiliation: Umeå Center for Molecular Medicine, Umeå University, Umeå, Sweden.

ABSTRACT
Although the function of the adult olfactory system has been thoroughly studied, the molecular mechanisms regulating the initial formation of the olfactory nerve, the first cranial nerve, remain poorly defined. Here, we provide evidence that both modulated Notch and bone morphogenetic protein (BMP) signaling affect the generation of neurons in the olfactory epithelium and reduce the number of migratory neurons, so called epithelioid cells. We show that this reduction of epithelial and migratory neurons is followed by a subsequent failure or complete absence of olfactory nerve formation. These data provide new insights into the early generation of neurons in the olfactory epithelium and the initial formation of the olfactory nerve tract. Our results present a novel mechanism in which BMP signals negatively affect Notch activity in a dominant manner in the olfactory epithelium, thereby regulating neurogenesis and explain why a balance of BMP and Notch activity is critical for the generation of neurons and proper development of the olfactory nerve.

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Notch activity is required to maintain Hes5 positive progenitor cells.(A) Schematic drawing depicting the explant method. Stage 14 olfactory placodal (OP) explants (green box) were isolated, separated from the head mesenchyme and cultured in vitro for different time points. (B) OP explants cultured for 7 h generated Hes5+ cells, but no or only a few Ngn1+ cells were detected (n = 12). (C) OP explants cultured for 7 h in the presence of DAPT (50 µM) generated many Ngn1+ precursors, but no Hes5+ progenitor cells (n = 12). (D, F) OP explants cultured for 24 (n = 20) and 40 h (n = 12) generated Hes5+, Ngn1+ and HuC/D+ cells throughout the explants. (E) OP explants cultured for 24 h in the presence of DAPT (50 µM) generated many Ngn1+ cells and HuC/D+ neurons, but no Hes5+ progenitor cells (n = 20). (G) OP explants cultured for 40 h in the presence of DAPT (50 µM) generated many HuC/D+ neurons, but no Hes5+ or Ngn1+ cells (n = 12).
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pone-0017379-g004: Notch activity is required to maintain Hes5 positive progenitor cells.(A) Schematic drawing depicting the explant method. Stage 14 olfactory placodal (OP) explants (green box) were isolated, separated from the head mesenchyme and cultured in vitro for different time points. (B) OP explants cultured for 7 h generated Hes5+ cells, but no or only a few Ngn1+ cells were detected (n = 12). (C) OP explants cultured for 7 h in the presence of DAPT (50 µM) generated many Ngn1+ precursors, but no Hes5+ progenitor cells (n = 12). (D, F) OP explants cultured for 24 (n = 20) and 40 h (n = 12) generated Hes5+, Ngn1+ and HuC/D+ cells throughout the explants. (E) OP explants cultured for 24 h in the presence of DAPT (50 µM) generated many Ngn1+ cells and HuC/D+ neurons, but no Hes5+ progenitor cells (n = 20). (G) OP explants cultured for 40 h in the presence of DAPT (50 µM) generated many HuC/D+ neurons, but no Hes5+ or Ngn1+ cells (n = 12).

Mentions: Neurogenesis in the olfactory epithelium occurs in an ordered manner with defined cell populations, such as progenitor cells, immediate neuronal precursors and post-mitotic neurons. To elucidate in more detail which cell population in the olfactory neuron lineage is initially affected by the loss of Notch activity, we established an explant assay of olfactory epithelial cell differentiation. Olfactory placodal (OP) explants of stage 14 chick embryos were cultured for different time points (Fig. 4A), alone or together with DAPT, an inhibitor of the γ-secretase enzyme, that catalyses the cleavage of the intracellular domain of Notch after ligand binding [25]. The underlying head mesenchyme was removed from the OP explants to avoid indirect effects from these cells. After culture, we analysed the expression of Hes5, Ngn1 and HuC/D.


A balance of BMP and notch activity regulates neurogenesis and olfactory nerve formation.

Maier E, Nord H, von Hofsten J, Gunhaga L - PLoS ONE (2011)

Notch activity is required to maintain Hes5 positive progenitor cells.(A) Schematic drawing depicting the explant method. Stage 14 olfactory placodal (OP) explants (green box) were isolated, separated from the head mesenchyme and cultured in vitro for different time points. (B) OP explants cultured for 7 h generated Hes5+ cells, but no or only a few Ngn1+ cells were detected (n = 12). (C) OP explants cultured for 7 h in the presence of DAPT (50 µM) generated many Ngn1+ precursors, but no Hes5+ progenitor cells (n = 12). (D, F) OP explants cultured for 24 (n = 20) and 40 h (n = 12) generated Hes5+, Ngn1+ and HuC/D+ cells throughout the explants. (E) OP explants cultured for 24 h in the presence of DAPT (50 µM) generated many Ngn1+ cells and HuC/D+ neurons, but no Hes5+ progenitor cells (n = 20). (G) OP explants cultured for 40 h in the presence of DAPT (50 µM) generated many HuC/D+ neurons, but no Hes5+ or Ngn1+ cells (n = 12).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044177&req=5

pone-0017379-g004: Notch activity is required to maintain Hes5 positive progenitor cells.(A) Schematic drawing depicting the explant method. Stage 14 olfactory placodal (OP) explants (green box) were isolated, separated from the head mesenchyme and cultured in vitro for different time points. (B) OP explants cultured for 7 h generated Hes5+ cells, but no or only a few Ngn1+ cells were detected (n = 12). (C) OP explants cultured for 7 h in the presence of DAPT (50 µM) generated many Ngn1+ precursors, but no Hes5+ progenitor cells (n = 12). (D, F) OP explants cultured for 24 (n = 20) and 40 h (n = 12) generated Hes5+, Ngn1+ and HuC/D+ cells throughout the explants. (E) OP explants cultured for 24 h in the presence of DAPT (50 µM) generated many Ngn1+ cells and HuC/D+ neurons, but no Hes5+ progenitor cells (n = 20). (G) OP explants cultured for 40 h in the presence of DAPT (50 µM) generated many HuC/D+ neurons, but no Hes5+ or Ngn1+ cells (n = 12).
Mentions: Neurogenesis in the olfactory epithelium occurs in an ordered manner with defined cell populations, such as progenitor cells, immediate neuronal precursors and post-mitotic neurons. To elucidate in more detail which cell population in the olfactory neuron lineage is initially affected by the loss of Notch activity, we established an explant assay of olfactory epithelial cell differentiation. Olfactory placodal (OP) explants of stage 14 chick embryos were cultured for different time points (Fig. 4A), alone or together with DAPT, an inhibitor of the γ-secretase enzyme, that catalyses the cleavage of the intracellular domain of Notch after ligand binding [25]. The underlying head mesenchyme was removed from the OP explants to avoid indirect effects from these cells. After culture, we analysed the expression of Hes5, Ngn1 and HuC/D.

Bottom Line: Here, we provide evidence that both modulated Notch and bone morphogenetic protein (BMP) signaling affect the generation of neurons in the olfactory epithelium and reduce the number of migratory neurons, so called epithelioid cells.These data provide new insights into the early generation of neurons in the olfactory epithelium and the initial formation of the olfactory nerve tract.Our results present a novel mechanism in which BMP signals negatively affect Notch activity in a dominant manner in the olfactory epithelium, thereby regulating neurogenesis and explain why a balance of BMP and Notch activity is critical for the generation of neurons and proper development of the olfactory nerve.

View Article: PubMed Central - PubMed

Affiliation: Umeå Center for Molecular Medicine, Umeå University, Umeå, Sweden.

ABSTRACT
Although the function of the adult olfactory system has been thoroughly studied, the molecular mechanisms regulating the initial formation of the olfactory nerve, the first cranial nerve, remain poorly defined. Here, we provide evidence that both modulated Notch and bone morphogenetic protein (BMP) signaling affect the generation of neurons in the olfactory epithelium and reduce the number of migratory neurons, so called epithelioid cells. We show that this reduction of epithelial and migratory neurons is followed by a subsequent failure or complete absence of olfactory nerve formation. These data provide new insights into the early generation of neurons in the olfactory epithelium and the initial formation of the olfactory nerve tract. Our results present a novel mechanism in which BMP signals negatively affect Notch activity in a dominant manner in the olfactory epithelium, thereby regulating neurogenesis and explain why a balance of BMP and Notch activity is critical for the generation of neurons and proper development of the olfactory nerve.

Show MeSH
Related in: MedlinePlus