The transcription factor Lmx1b maintains Wnt1 expression within the isthmic organizer

Development ◽  
2000 ◽  
Vol 127 (9) ◽  
pp. 1857-1867 ◽  
Author(s):  
K.A. Adams ◽  
J.M. Maida ◽  
J.A. Golden ◽  
R.D. Riddle
Keyword(s):  
Transcription Factor ◽  
Neural Tube ◽  
Morphological Changes ◽  
Distinct Region ◽  
Expression Domain ◽  
Similar Phenotype ◽  
Signaling Center ◽  
Wnt1 Expression

Cells in the caudal mesencephalon and rostral metencephalon become organized by signals emanating from the isthmus organizer (IsO). The IsO is associated with the isthmus, a morphological constriction of the neural tube which eventually defines the mesencephalic/ metencephalic boundary (MMB). Here we report that the transcription factor Lmx1b is expressed and functions in a distinct region of the IsO. Lmx1b expression is maintained by the glycoprotein Fgf8, a signal capable of mediating IsO signaling. Lmx1b, in turn, maintains the expression of the secreted factor Wnt1. Our conclusions are substantiated by the following: (i) Lmx1b mRNA becomes localized to the isthmus immediately after Fgf8 initiation, (ii) Wnt1 expression is localized to the Lmx1b expression domain, but with slightly later kinetics, (iii) Fgf8-soaked beads generate similar domains of expression for Lmx1b and Wnt1 and (iv) retroviral-mediated expression of Lmx1b (Lmx1b/RCAS) maintains Wnt1 expression in the mesencephalon. Ectopic Lmx1b is insufficient to alter the expression of a number of other genes expressed at the IsO, suggesting that it does not generate a new signaling center. Instead, if we allow Lmx1b/RCAS-infected brains to develop longer, we detect changes in mesencephalic morphology. Since both ectopic and endogenous Lmx1b expression occurs in regions of the isthmus undergoing morphological changes, it could normally play a role in this process. Furthermore, a similar phenotype is not observed in Wnt1/RCAS-infected brains, demonstrating that ectopic Wnt1 is insufficient to mediate the effect of ectopic Lmx1b in our assay. Since Wnt1 function has been linked to the proper segregation of mesencephalic and metencephalic cells, we suggest that Lmx1b and Wnt1 normally function in concert to affect IsO morphogenesis.

FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1189-1200 ◽  
Author(s):  
S. Martinez ◽  
P.H. Crossley ◽  
I. Cobos ◽  
J.L. Rubenstein ◽  
G.R. Martin
Keyword(s):  
Neural Tube ◽  
Lateral Wall ◽  
Mirror Image ◽  
Repressive Effect ◽  
Isthmic Nuclei ◽  
Signaling Center ◽  
The One ◽  
The Brain ◽  
Morphogenetic Effects ◽  
Wnt1 Expression

Beads containing recombinant FGF8 (FGF8-beads) were implanted in the prospective caudal diencephalon or midbrain of chick embryos at stages 9–12. This induced the neuroepithelium rostral and caudal to the FGF8-bead to form two ectopic, mirror-image midbrains. Furthermore, cells in direct contact with the bead formed an outgrowth that protruded laterally from the neural tube. Tissue within such lateral outgrowths developed proximally into isthmic nuclei and distally into a cerebellum-like structure. These morphogenetic effects were apparently due to FGF8-mediated changes in gene expression in the vicinity of the bead, including a repressive effect on Otx2 and an inductive effect on En1, Fgf8 and Wnt1 expression. The ectopic Fgf8 and Wnt1 expression domains formed nearly complete concentric rings around the FGF8-bead, with the Wnt1 ring outermost. These observations suggest that FGF8 induces the formation of a ring-like ectopic signaling center (organizer) in the lateral wall of the brain, similar to the one that normally encircles the neural tube at the isthmic constriction, which is located at the boundary between the prospective midbrain and hindbrain. This ectopic isthmic organizer apparently sends long-range patterning signals both rostrally and caudally, resulting in the development of the two ectopic midbrains. Interestingly, our data suggest that these inductive signals spread readily in a caudal direction, but are inhibited from spreading rostrally across diencephalic neuromere boundaries. These results provide insights into the mechanism by which FGF8 induces an ectopic organizer and suggest that a negative feedback loop between Fgf8 and Otx2 plays a key role in patterning the midbrain and anterior hindbrain.

scholarly journals Transcription factor TEAD2 is involved in neural tube closure

genesis ◽  
2007 ◽  
Vol 45 (9) ◽  
pp. 577-587 ◽  
Author(s):  
Kotaro J. Kaneko ◽  
Matthew J. Kohn ◽  
Chengyu Liu ◽  
Melvin L. DePamphilis
Keyword(s):  
Transcription Factor ◽  
Neural Tube ◽  
Neural Tube Closure ◽  
Tube Closure

scholarly journals Effect of aging on UVC-induced apoptosis of rat splenocytes.

2000 ◽  
Vol 47 (2) ◽  
pp. 339-347 ◽  
Author(s):  
E Radziszewska ◽  
K Piwocka ◽  
A Bielak-Zmijewska ◽  
J Skierski ◽  
E Sikora
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Morphological Changes ◽  
Transcription Factor Activity ◽  
Factor Activity ◽  
Dna Ladder ◽  
Young Rats ◽  
Bax Protein ◽  
Old Rats ◽  
Induced Apoptosis

UVC-induced apoptotic symptoms such as morphological changes, DNA fragmentation, Bcl-2 and Bax protein expression were examined in primary splenocyte cultures from young (3 months) and old (24 months) rats. The activities of AP-1 and CRE transcription factors in UVC-irradiated splenocytes were also assessed. At 24 h after UVC irradiation 40% of cells derived from young rats were found to be apoptotic, which was twice as much as in splenocytes from old rats. Apoptosis in cells from old rats did not give typical symptoms like a "DNA ladder" and Bcl-2 protein downregulation, in contrast to splenocytes from young rats. No AP-1 transcription factor activity was found in UVC-irradiated splenocytes from old animals and only a trace activity in splenocytes from young animals. This indicates that, UVC-induced apoptosis in rat splenocytes is practically AP-1 independent and that cells from old rats are less sensitive to UVC irradiation than splenocytes from young rats.

Heart tube patterning in Drosophila requires integration of axial and segmental information provided by the Bithorax Complex genes and hedgehog signaling

Development ◽  
2002 ◽  
Vol 129 (19) ◽  
pp. 4509-4521 ◽  
Author(s):  
Romina Ponzielli ◽  
Martine Astier ◽  
Aymeric Chartier ◽  
Armel Gallet ◽  
Pascal Thérond ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Spatial Information ◽  
Morphological Changes ◽  
Cardiac Cells ◽  
Homeotic Genes ◽  
Bithorax Complex ◽  
Heart Tube ◽  
Expression Domain ◽  
Axial Patterning ◽  
On Line

The Drosophila larval cardiac tube is composed of 104 cardiomyocytes that exhibit genetic and functional diversity. The tube is divided into the aorta and the heart proper that encompass the anterior and posterior parts of the tube, respectively. Differentiation into aorta and heart cardiomyocytes takes place during embryogenesis. We have observed living embryos to correlate morphological changes occurring during the late phases of cardiogenesis with the acquisition of organ function, including functional inlets, or ostiae. Cardiac cells diversity originates in response to two types of spatial information such that cells differentiate according to their position, both within a segment and along the anteroposterior axis. Axial patterning is controlled by homeotic genes of the Bithorax Complex (BXC) which are regionally expressed within the cardiac tube in non-overlapping domains. Ultrabithorax (Ubx) is expressed in the aorta whereas abdominal A (abd-A) is expressed in the heart, with the exception of the four most posterior cardiac cells which express Abdominal B (Abd-B). Ubx and abd-A functions are required to confer an aorta or a heart identity on cardiomyocytes, respectively. The anterior limit of the expression domain of Ubx, abd-A and Abd-B is independent of the function of the other genes. In contrast, abd-A represses Ubx expression in the heart and ectopic overexpression of abd-A transforms aorta cells into heart cardiomyocytes. Taken together, these results support the idea that BXC homeotic genes in the cardiac tube conform to the posterior prevalence rule. The cardiac tube is also segmentally patterned and each metamere contains six pairs of cardioblasts that are genetically diverse. We show that the transcription of seven up (svp), which is expressed in the two most posterior pairs of cardioblasts in each segment, is dependent on hedgehog (hh) signaling from the dorsal ectoderm. In combination with the axial information furnished by abd-A, the segmental hh-dependent information leads to the differentiation of the six pairs of svp-expressing cells into functional ostiae. Movies available on-line

Different contributions of pannier and wingless to the patterning of the dorsal mesothorax of Drosophila

Development ◽  
1999 ◽  
Vol 126 (16) ◽  
pp. 3523-3532 ◽  
Author(s):  
M.J. Garcia-Garcia ◽  
P. Ramain ◽  
P. Simpson ◽  
J. Modolell
Keyword(s):  
Transcription Factor ◽  
Concentration Gradient ◽  
Positional Information ◽  
Secreted Protein ◽  
Expression Domain ◽  
Similar Role ◽  
Finger Protein ◽  
Proneural Cluster ◽  
Gata Family ◽  
Permissive Role

In Drosophila, the GATA family transcription factor Pannier and the Wnt secreted protein Wingless are known to be important for the patterning of the notum, a part of the dorsal mesothorax of the fly. Thus, both proteins are necessary for the development of the dorsocentral mechanosensory bristles, although their roles in this process have not been clarified. Here, we show that Pannier directly activates the proneural genes achaete and scute by binding to the enhancer responsible for the expression of these genes in the dorsocentral proneural cluster. Moreover, the boundary of the expression domain of Pannier appears to delimit the proneural cluster laterally, while antagonism of Pannier function by the Zn-finger protein U-shaped sets its limit dorsally. So, Pannier and U-shaped provide positional information for the patterning of the dorsocentral cluster. In contrast and contrary to previous suggestions, Wingless does not play a similar role, since the levels and vectorial orientation of its concentration gradient in the dorsocentral area can be greatly modified without affecting the position of the dorsocentral cluster. Thus, Wingless has only a permissive role on dorsocentral achaete-scute expression. We also provide evidence indicating that Pannier and U-shaped are main effectors of the regulation of wingless expression in the presumptive notum.

BMP signaling patterns the dorsal and intermediate neural tube via regulation of homeobox and helix-loop-helix transcription factors

Development ◽  
2002 ◽  
Vol 129 (10) ◽  
pp. 2459-2472 ◽  
Author(s):  
John R. Timmer ◽  
Charlotte Wang ◽  
Lee Niswander
Keyword(s):  
Transcription Factors ◽  
Neural Tube ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Neural Cell ◽  
Bmp Signaling ◽  
Expression Domain ◽  
Cell Identity ◽  
Dorsoventral Axis ◽  
Helix Loop Helix

In the spinal neural tube, populations of neuronal precursors that express a unique combination of transcription factors give rise to specific classes of neurons at precise locations along the dorsoventral axis. Understanding the patterning mechanisms that generate restricted gene expression along the dorsoventral axis is therefore crucial to understanding the creation of diverse neural cell types. Bone morphogenetic proteins (BMPs) and other transforming growth factor β (TGFβ) proteins are expressed by the dorsal-most cells of the neural tube (the roofplate) and surrounding tissues, and evidence indicates that they play a role in assigning cell identity. We have manipulated the level of BMP signaling in the chicken neural tube to show that BMPs provide patterning information to both dorsal and intermediate cells. BMP regulation of the expression boundaries of the homeobox proteins Pax6, Dbx2 and Msx1 generates precursor populations with distinct developmental potentials. Within the resulting populations, thresholds of BMP act to set expression domain boundaries of developmental regulators of the homeobox and basic helix-loop-helix (bHLH) families, ultimately leading to the generation of a diversity of differentiated neural cell types. This evidence strongly suggests that BMPs are the key regulators of dorsal cell identity in the spinal neural tube.

scholarly journals Pharmacological Transdifferentiation of Human Nasal Olfactory Stem Cells into Dopaminergic Neurons

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Audrey Chabrat ◽  
Emmanuelle Lacassagne ◽  
Rodolphe Billiras ◽  
Sophie Landron ◽  
Amélie Pontisso-Mahout ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Dopaminergic Neurons ◽  
Adult Stem Cells ◽  
Morphological Changes ◽  
Direct Conversion ◽  
Patient Specific ◽  
Induced Pluripotent

The discovery of novel drugs for neurodegenerative diseases has been a real challenge over the last decades. The development of patient- and/or disease-specific in vitro models represents a powerful strategy for the development and validation of lead candidates in preclinical settings. The implementation of a reliable platform modeling dopaminergic neurons will be an asset in the study of dopamine-associated pathologies such as Parkinson’s disease. Disease models based on cell reprogramming strategies, using either human-induced pluripotent stem cells or transcription factor-mediated transdifferentiation, are among the most investigated strategies. However, multipotent adult stem cells remain of high interest to devise direct conversion protocols and establish in vitro models that could bypass certain limitations associated with reprogramming strategies. Here, we report the development of a six-step chemically defined protocol that drives the transdifferentiation of human nasal olfactory stem cells into dopaminergic neurons. Morphological changes were progressively accompanied by modifications matching transcript and protein dopaminergic signatures such as LIM homeobox transcription factor 1 alpha (LMX1A), LMX1B, and tyrosine hydroxylase (TH) expression, within 42 days of differentiation. Phenotypic changes were confirmed by the production of dopamine from differentiated neurons. This new strategy paves the way to develop more disease-relevant models by establishing reprogramming-free patient-specific dopaminergic cell models for drug screening and/or target validation for neurodegenerative diseases.

scholarly journals Visualization of bHLH transcription factor interactions in living mammalian cell nuclei and developing chicken neural tube by FRET

Cell Research ◽  
2006 ◽  
Vol 16 (6) ◽  
pp. 585-598 ◽  
Author(s):  
Chen Wang ◽  
Wei Bian ◽  
Caihong Xia ◽  
Ting Zhang ◽  
Francois Guillemot ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mammalian Cell ◽  
Neural Tube ◽  
Bhlh Transcription Factor ◽  
Cell Nuclei ◽  
Factor Interactions

scholarly journals spiel ohne grenzen/pou2is required during establishment of the zebrafish midbrain-hindbrain boundary organizer

Development ◽  
2001 ◽  
Vol 128 (21) ◽  
pp. 4165-4176 ◽  
Author(s):  
Heinz-Georg Belting ◽  
Giselbert Hauptmann ◽  
Dirk Meyer ◽  
Salim Abdelilah-Seyfried ◽  
Ajay Chitnis ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Ectopic Expression ◽  
Regional Identity ◽  
Positional Information ◽  
Neural Plate ◽  
Pou Domain ◽  
Normal Expression ◽  
Organizing Center ◽  
Wnt1 Expression ◽  
Permissive Role

The vertebrate midbrain-hindbrain boundary (MHB) organizes patterning and neuronal differentiation in the midbrain and anterior hindbrain. Formation of this organizing center involves multiple steps, including positioning of the MHB within the neural plate, establishment of the organizer and maintenance of its regional identity and signaling activities. Juxtaposition of the Otx2 and Gbx2 expression domains positions the MHB. How the positional information is translated into activation of Pax2, Wnt1 and Fgf8 expression during MHB establishment remains unclear. In zebrafish spiel ohne grenzen (spg) mutants, the MHB is not established, neither isthmus nor cerebellum form, the midbrain is reduced in size and patterning abnormalities develop within the hindbrain. In spg mutants, despite apparently normal expression of otx2, gbx1 and fgf8 during late gastrula stages, the initial expression of pax2.1, wnt1 and eng2, as well as later expression of fgf8 in the MHB primordium are reduced. We show that spg mutants have lesions in pou2, which encodes a POU-domain transcription factor. Maternal pou2 transcripts are distributed evenly in the blastula, and zygotic expression domains include the midbrain and hindbrain primordia during late gastrulation. Microinjection of pou2 mRNA can rescue pax2.1 and wnt1 expression in the MHB of spg/pou2 mutants without inducing ectopic expression. This indicates an essential but permissive role for pou2 during MHB establishment. pou2 is expressed normally in noi/pax2.1 and ace/fgf8 zebrafish mutants, which also form no MHB. Thus, expression of pou2 does not depend on fgf8 and pax2.1. Our data suggest that pou2 is required for the establishment of the normal expression domains of wnt1 and pax2.1 in the MHB primordium.

scholarly journals Trem2promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions

2018 ◽  
Author(s):  
Wenfei Liu ◽  
Orjona Taso ◽  
Rui Wang ◽  
Sevinc Bayram ◽  
Pablo Garcia-Reitboeck ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Inflammatory Responses ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Similar Expression Profile ◽  
Inflammatory Conditions ◽  
Phenotype Comparison ◽  
Inflammatory Phenotype ◽  
Similar Phenotype ◽  
Anti Inflammatory

AbstractGenome-wide association studies have reported that, amongst other microglial genes, variants inTREM2can profoundly increase the incidence of developing Alzheimer’s disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decreaseTrem2expression, and in parallel from knock-in mice heterozygous or homozygous for theTrem2R47H AD risk variant. The prevailing phenotype ofTrem2R47H knock-in mice was decreased expression levels ofTrem2in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reducedTrem2expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreasedTrem2expression under conditions of LPS pro-inflammatory or IL-4 anti-inflammatory stimulation revealed the importance ofTrem2in driving a number of the genes up-regulated in the anti-inflammatory phenotype. RNA-seq analysis showed that IL-4 induced the expression of a programme of genes includingArg1andAp1b1in microglia, which showed an attenuated response to IL-4 whenTrem2expression was decreased. Genes showing a similar expression profile toArg1were enriched for STAT6 transcription factor recognition elements in their promoter, andTrem2knockdown decreased levels of the transcription factor STAT6. LPS-induced pro-inflammatory stimulation suppressedTrem2expression, thus preventing TREM2’s anti-inflammatory drive. Given that anti-inflammatory signaling is associated with tissue repair, understanding the signaling mechanisms downstream ofTrem2in coordinating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL-4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease.Graphical abstract

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