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The Lim homeobox gene Lhx2 is required for olfactory sensory neuron identity.
Umeå University, Faculty of Medicine, Molecular Biology.
Umeå University, Faculty of Medicine, Molecular Biology.
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). (Bohm)
2004 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 131, no 21, 5319-5326 p.Article in journal (Refereed) Published
Abstract [en]

Progenitor cells in the mouse olfactory epithelium generate over a thousand subpopulations of neurons, each expressing a unique odorant receptor (OR) gene. This event is under the control of spatial cues, since neurons in different epithelial regions are restricted to express region-specific subsets of OR genes. We show that progenitors and neurons express the LIM-homeobox gene Lhx2 and that neurons in Lhx2-null mutant embryos do not diversify into subpopulations expressing different OR genes and other region-restricted genes such as Nqo1 and Ncam2. Lhx2-/- embryos have, however, a normal distribution of Mash1-positive and neurogenin 1-positive neuronal progenitors that leave the cell cycle, acquire pan-neuronal traits and form axon bundles. Increased cell death in combination with increased expression of the early differentiation marker Neurod1, as well as reduced expression of late differentiation markers (Galphaolf and Omp), suggests that neuronal differentiation in the absence of Lhx2 is primarily inhibited at, or immediate prior to, onset of OR expression. Aberrant regional expression of early and late differentiation markers, taken together with unaltered region-restricted expression of the Msx1 homeobox gene in the progenitor cell layer of Lhx2-/- embryos, shows that Lhx2 function is not required for all aspects of regional specification of progenitors and neurons. Thus, these results indicate that a cell-autonomous function of Lhx2 is required for differentiation of progenitors into a heterogeneous population of individually and regionally specified mature olfactory sensory neurons.

Place, publisher, year, edition, pages
2004. Vol. 131, no 21, 5319-5326 p.
Keyword [en]
Animals, Apoptosis, Cell Differentiation, Embryo/metabolism, Gene Expression Regulation; Developmental, Homeodomain Proteins/genetics/*metabolism, Immunohistochemistry, In Situ Hybridization, Mice, Mice; Knockout, NADPH Dehydrogenase/genetics/metabolism, Neural Cell Adhesion Molecules/genetics/metabolism, Neurons/*cytology/*metabolism, Olfactory Bulb/*cytology/embryology/*metabolism, Receptors; Odorant/metabolism, Stem Cells/cytology/metabolism, Transcription Factors/deficiency/genetics/*metabolism
National Category
Medical and Health Sciences
URN: urn:nbn:se:umu:diva-16625DOI: 10.1242/dev.01416PubMedID: 15456728OAI: diva2:156298
Available from: 2007-10-08 Created: 2007-10-08 Last updated: 2010-08-02Bibliographically approved
In thesis
1. The Role of Lhx2 During Organogenesis: - Analysis of the Hepatic, Hematopoietic and Olfactory Systems
Open this publication in new window or tab >>The Role of Lhx2 During Organogenesis: - Analysis of the Hepatic, Hematopoietic and Olfactory Systems
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During embryonic development a variety of tissues and organs such as the lung, eye, and kidney are being formed. The generation of functional organs is regulated by reciprocal cell-cell interactions. Via the secretion of soluble molecules one type of cells affect the fate of their neighboring cells. A central issue in organogenesis is how a cell interprets such extrinsic signals and adopts a specific fate, and how the cell in response to this signal establishes reciprocal signaling. Transcription factors play a critical role in this process and my thesis focuses on the role of the LIM-homeodomain transcription factor, Lhx2, in the development of three different organ systems, the liver, the hematopoietic system and the olfactory system.

The liver is formed from endoderm of the ventral foregut and mesenchyme of the septum transversum (st) and its development depends upon signaling interactions between these two tissues. As the liver becomes a distinct organ it is colonized by hematopoietic cells and serves as hematopoietic organ until birth. The fetal liver provides a microenvironment that supports the expansion of the entire hematopoietic system (HS) including the hematopoietic stem cells (HSCs). Liver development in Lhx2-/- embryos is disrupted leading to a lethal anemia due to insufficient support of hematopoiesis. To further investigate the role of Lhx2 in liver development I analyzed gene expression from the Lhx2 locus during liver development in wild-type and Lhx2-/- mice. Lhx2 is expressed in the liver associated st mesenchymal cells that become integrated in the liver and contribute to a subpopulation of hepatic stellate cells in adult liver. Lhx2 is not required for the formation of these mesenchymal cells, suggesting that the phenotype in Lhx2-/- livers is due to the presence of defective mesenchymal cells. The putative role of Lhx2 in the expansion of the HS was examined by introducing Lhx2 cDNA into embryonic stem cells differentiated in vitro. This approach allowed for the generation of immortalized multipotent hematopoietic progenitor cell (HPC) lines that share many characteristics with normal HSCs. The Lhx2-dependent generation of HSC-like cell lines suggests that Lhx2 plays a role in the maintenance and/or expansion of the HS. To isolate genes putatively linked to Lhx2 function, genes differentially expressed in the HPC lines were isolated using a cDNA subtraction approach. This allowed for the identification of a few genes putatively linked to Lhx2 function, as well as several stem cell-specific genes. The antagonist of Wnt signalling, Dickkopf-1 (Dkk-1), was identified in the former group of genes as it showed a similar expression pattern in the fetal liver, as that of Lhx2 and expression of Dkk-1 in fetal liver and in HPC lines appeared to be regulated by Lhx2. This suggests that Dkk-1 plays a role in liver development and/or HSC physiology during embryonic development.

During development of the olfactory epithelium (OE) neuronal progenitors differentiate into mature olfactory sensory neurons (OSNs) that are individually specified into over a thousand different subpopulations, each expressing a unique odorant receptor (OR) gene. The expression of Lhx2 in olfactory neurons suggested a potential role for Lhx2 in the development of OSNs. To address this OE from Lhx2-/- and wild-type mice was compared. In the absence of functional Lhx2 neuronal differentiation was arrested prior to onset of OR expression. Lhx2 is thus required for the development of OSN progenitors into functional, individually specified OSNs.

Thus, Lhx2 trigger a variety of cellular responses in different organ systems that play important roles in organ development in vivo and stem cell expansion in vitro.

61 p.
Developmental biology, LIM-homeobox gene, Lhx2, fetal liver, hepatic stellate cells, hematopoietic stem cells, septum transversum, self-renewal, odorant receptor genes, olfactory epithelium, olfactory sensory neuron, Utvecklingsbiologi
National Category
Developmental Biology
Research subject
Molecular Biology
urn:nbn:se:umu:diva-306 (URN)91-7305-693-6 (ISBN)
Public defence
2004-09-24, E04, 6M, Norrlands Universitetssjukhus, Umeå, 09:00
Available from: 2004-09-01 Created: 2004-09-01 Last updated: 2010-08-02Bibliographically approved

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Kolterud, ÅsaAlenius, MattiasCarlsson, LeifBohm, Staffan
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