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The Role of Lhx2 During Organogenesis: - Analysis of the Hepatic, Hematopoietic and Olfactory Systems
Umeå University, Faculty of Medicine, Molecular Biology.
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.

Place, publisher, year, edition, pages
2004. , 61 p.
Keyword [en]
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
Keyword [sv]
Utvecklingsbiologi
National Category
Developmental Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-306ISBN: 91-7305-693-6 (print)OAI: oai:DiVA.org:umu-306DiVA: diva2:143025
Public defence
2004-09-24, E04, 6M, Norrlands Universitetssjukhus, Umeå, 09:00
Opponent
Supervisors
Available from: 2004-09-01 Created: 2004-09-01 Last updated: 2010-08-02Bibliographically approved
List of papers
1. Lhx2 is expressed in the septum transversum mesenchyme that becomes an integral part of the liver and the formation of these cells is independent of functional Lhx2.
Open this publication in new window or tab >>Lhx2 is expressed in the septum transversum mesenchyme that becomes an integral part of the liver and the formation of these cells is independent of functional Lhx2.
2004 (English)In: Gene Expression Patterns, ISSN 1567-133X, E-ISSN 1872-7298, Vol. 4, no 5, 521-528 p.Article in journal (Refereed) Published
Abstract [en]

Liver development is based on reciprocal interactions between ventral foregut endoderm and adjacent mesenchymal tissues. Targeted disruption of the LIM-homeobox gene Lhx2 has revealed that it is important for the expansion of the liver during embryonic development, whereas it appears not to be involved in the induction of hepatic fate. It is not known whether Lhx2 is expressed in the endodermal or mesenchymal portion of the liver, or if the cells normally expressing Lhx2 are absent or present in the liver of Lhx2(-/-) embryos. To address this we have analyzed gene expression from the Lhx2 locus during hepatic development in wild type and Lhx2(-/-) mice. Lhx2 is expressed in cells of the septum transversum mesenchyme adjacent to the liver bud from embryonic day 9. The hepatic cords subsequently migrate into and intermingle with the Lhx2+ cells of the septum transversum mesenchyme. Lhx2 expression is thereafter maintained in a subpopulation of mesenchymal cells in the liver until adult life. In adult liver the Lhx2+ mesenchymal cells co-express desmin, a marker associated with stellate cells. At embryonic day 10.5, cells expressing the mutant Lhx2 allel are present in Lhx2(-/-) livers, and expression of Hlx, hepatocyte growth factor, Hex and Prox1, genes known to be important in liver development, is independent of functional Lhx2 expression. Thus, Lhx2 is specifically expressed in the liver-associated septum transversum mesenchyme that subsequently becomes an integral part of the liver and the formation of these mesenchymal cells does not require functional Lhx2.

Keyword
Bone morphogenetic proteins; Desmin; Embryonic development; Epithelial–mesenchymal interactions; Fetal liver; Foregut diverticulum; Hex; Hepatocyte growth factor; Hlx; Ito cell; Liver bud; Lhx2; Lhx2 mutant phenotype; LIM-homeobox gene; Prox1; Septum transversum mesenchyme; Stellate cells; Transcription factor; Ventral foregut endoderm; Vimentin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-4064 (URN)10.1016/j.modgep.2004.03.001 (DOI)15261829 (PubMedID)
Available from: 2004-09-01 Created: 2004-09-01 Last updated: 2017-12-14Bibliographically approved
2. Expression of the LIM-homeobox gene LH2 generates immortalized Steel factor-dependent multipotent hematopoietic precursors
Open this publication in new window or tab >>Expression of the LIM-homeobox gene LH2 generates immortalized Steel factor-dependent multipotent hematopoietic precursors
1998 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 17, no 19, 5744-5756 p.Article in journal (Refereed) Published
Abstract [en]

The genes controlling self-renewal and differentiation in the hematopoietic system are largely unknown. The LIM-homeobox genes are known to be important for asymmetric cell divisions and differentiation of specific cell types and organs. One member of this family, LH2, is expressed in fetal liver at the time of active hematopoiesis. Therefore, we have assessed the function of LH2 during the formation and initial expansion of the hematopoietic system by differentiating LH2-transduced embryonic stem (ES) cells in vitro. This procedure generated multipotent hematopoietic precursor cell (HPC) lines that required Steel factor for growth. HPC lines have been maintained in an undifferentiated state in culture for >7 months. Other growth factors tested efficiently induce terminal differentiation of HPCs into various mature myeloid lineages. Steel factor is also required and acts synergistically with the other growth factors to generate multilineage colonies from the HPCs. These HPC lines express transcription factors that are consistent with an immature progenitor, and the pattern of cell surface marker expression is similar to that of early fetal multipotent hematopoietic progenitors. Collectively, these data suggest that the HPC lines represent an early fetal multipotent hematopoietic progenitor, and suggest a role for LH2 in the control of cell fate decision and/or proliferation in the hematopoietic system.

Keyword
ES cells, LIM-homeobox gene, multipotent hematopoietic precursor, self-renewal versus differentiation, Steel factor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-4065 (URN)10.1093/emboj/17.19.5744 (DOI)9755174 (PubMedID)
Available from: 2004-09-01 Created: 2004-09-01 Last updated: 2017-12-14Bibliographically approved
3. Identification and characterization of genes specifically expressed in hematopoietic progenitor/stem cells immortalized by Lhx2
Open this publication in new window or tab >>Identification and characterization of genes specifically expressed in hematopoietic progenitor/stem cells immortalized by Lhx2
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4066 (URN)
Available from: 2004-09-01 Created: 2004-09-01 Last updated: 2010-01-13Bibliographically approved
4. The Lim homeobox gene Lhx2 is required for olfactory sensory neuron identity.
Open this publication in new window or tab >>The Lim homeobox gene Lhx2 is required for olfactory sensory neuron identity.
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.

Keyword
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
Identifiers
urn:nbn:se:umu:diva-16625 (URN)10.1242/dev.01416 (DOI)15456728 (PubMedID)
Available from: 2007-10-08 Created: 2007-10-08 Last updated: 2017-12-14Bibliographically approved

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