| 1. |
- Allan, Douglas W, et al.
(författare)
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Specification of Neuropeptide Cell Identity by the Integration of Retrograde BMP Signaling and a Combinatorial Transcription Factor Code
- 2003
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Ingår i: Cell. - Cambridge, United States : Cell Press. - 0092-8674 .- 1097-4172. ; 113:1, s. 73-86
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Tidskriftsartikel (refereegranskat)abstract
- Individual neurons express only one or a few of the many identified neurotransmitters and neuropeptides, but the molecular mechanisms controlling their selection are poorly understood. In the Drosophila ventral nerve cord, the six Tv neurons express the neuropeptide gene FMRFamide. Each Tv neuron resides within a neuronal cell group specified by the LIM-homeodomain gene apterous. We find that the zinc-finger gene squeeze acts in Tv cells to promote their unique axon pathfinding to a peripheral target. There, the BMP ligand Glass bottom boat activates the Wishful thinking receptor, initiating a retrograde BMP signal in the Tv neuron. This signal acts together with apterous and squeeze to activate FMRFamide expression. Reconstituting this "code," by combined BMP activation and apterous/squeeze misexpression, triggers ectopic FMRFamide expression in peptidergic neurons. Thus, an intrinsic transcription factor code integrates with an extrinsic retrograde signal to select a specific neuropeptide identity within peptidergic cells.
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| 2. |
- Certel, S.J., et al.
(författare)
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Specification of Drosophila motoneuron identity by the combinatorial action of POU and LIM-HD factors
- 2004
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 131:21, s. 5429-5439
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Tidskriftsartikel (refereegranskat)abstract
- In both vertebrates and invertebrates, members of the LIM-homeodomain (LIM-HD) family of transcription factors act in combinatorial codes to specify motoneuron subclass identities. In the developing Drosophila embryo, the LIM-HD factors Islet (Tailup) and Lim3, specify the set of motoneuron subclasses that innervate ventral muscle targets. However, as several subclasses express both Islet and Lim3, this combinatorial code alone cannot explain how these motoneuron groups are further differentiated. To identify additional factors that may act to refine this LIM-HD code, we have analyzed the expression of POU genes in the Drosophila embryonic nerve cord. We find that the class III POU protein, Drifter (Ventral veinless), is co-expressed with Islet and Lim3 specifically in the ISNb motoneuron subclass. Loss-of-function and misexpression studies demonstrate that the LIM-HD combinatorial code requires Drifter to confer target specificity between the ISNb and TN motoneuron subclasses. To begin to elucidate molecules downstream of the LIM-HD code, we examined the involvement of the Beaten path (Beat) family of immunoglobulin-containing cell-adhesion molecules. We find that beat Ic genetically interacts with islet and Lim3 in the TN motoneuron subclass and can also rescue the TN fasciculation defects observed in islet and Lim3 mutants. These results suggest that in the TN motoneuron context, Islet and Lim3 may specify axon target selection through the actions of IgSF call-adhesion molecules.
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| 3. |
- Kolterud, Åsa, 1973-
(författare)
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The Role of Lhx2 During Organogenesis : - Analysis of the Hepatic, Hematopoietic and Olfactory Systems
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 4. |
- Miguel-Aliaga, I., et al.
(författare)
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Independent roles of the dachshund and eyes absent genes in BMP signaling, axon pathfinding and neuronal specification
- 2004
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 131:23, s. 5837-5848
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Tidskriftsartikel (refereegranskat)abstract
- In the Drosophila nerve cord, a subset of neurons expresses the neuropeptide FMRFamide related (Fmrf). Fmrf expression is controlled by a combinatorial code of intrinsic factors and an extrinsic BMP signal. However, this previously identified code does not fully explain the regulation of Fmrf. We have found that the Dachshund (Dac) and Eyes Absent (Eya) transcription co-factors participate in this combinatorial code. Previous studies have revealed an intimate link between Dac and Eya during eye development. Here, by analyzing their function in neurons with multiple phenotypic markers, we demonstrate that they play independent roles in neuronal specification, even within single cells. dac is required for high-level Fmrf expression, and acts potently together with apterous and BMP signaling to trigger Fmrf expression ectopically, even in motoneurons. By contrast, eya regulates Fmrf expression by controlling both axon pathfinding and BMP signaling, but cannot trigger Fmrf ectopically. Thus, we show that dac and eya perform entirely different functions in a single cell type to ultimately regulate a single phenotypic outcome.
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| 5. |
- Miguel-Aliaga, Irene, et al.
(författare)
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Segment-specific prevention of pioneer neuron apoptosis by cell-autonomous, postmitotic Hox gene activity
- 2004
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 131:24, s. 6093-6105
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Tidskriftsartikel (refereegranskat)abstract
- In vertebrates, neurons often undergo apoptosis after differentiating and extending their axons. By contrast, in the developing nervous system of invertebrate embryos apoptosis typically occurs soon after cells are generated. Here, we show that the Drosophila dMP2 and MP1 pioneer neurons undergo segment-specific apoptosis at late embryonic stages, long after they have extended their axons and have performed their pioneering role in guiding follower axons. This segmental specificity is achieved by differential expression of the Hox gene Abdominal B, which in posterior segments prevents pioneer neuron death postmitotically and cell-autonomously by repressing the RHG-motif cell death activators reaper and grim. Our results identify the first clear case of a cell-autonomous and anti-apoptotic role for a Hox gene in vivo. In addition, they provide a novel mechanism linking Hox positional information to differences in neuronal architecture along the anteroposterior axis by the selective elimination of mature neurons.
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