N-terminal fatty-acylation of sonic hedgehog enhances the induction of rodent ventral forebrain neurons

Development ◽  
2001 ◽  
Vol 128 (12) ◽  
pp. 2351-2363 ◽  
Author(s):  
Jhumku D. Kohtz ◽  
Hae Young Lee ◽  
Nicholas Gaiano ◽  
Joshua Segal ◽  
Evan Ng ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Ectopic Expression ◽  
Wild Type ◽  
Ganglionic Eminence ◽  
Fatty Acylation ◽  
Lateral Ganglionic Eminence ◽  
Ganglionic Eminences ◽  
Islet 1 ◽  
The Brain ◽  
Sequential Induction

The adult basal ganglia arise from the medial and lateral ganglionic eminences, morphologically distinct structures found in the embryonic telencephalon. We have previously shown that temporal changes in sonic hedgehog (Shh) responsiveness determine the sequential induction of embryonic neurons that populate the medial and lateral ganglionic eminences. In this report, we show that Shh-mediated differentiation of neurons that populate the lateral ganglionic eminence express different combinations of the homeobox-containing transcription factors Dlx, Mash1 and Islet 1/2. Furthermore, we show that N-terminal fatty-acylation of Shh significantly enhances its ability to induce the differentiation of rat E11 telencephalic neurons expressing Dlx, Islet 1/2 or Mash1. Recent evidence indicates that in utero injection of the E9.5 mouse forebrain with retroviruses encoding wild-type Shh induces the ectopic expression of Dlx2 and severe deformities in the brain. In this report, we show that Shh containing a mutation at the site of acylation prevents either of these phenotypes. These results suggest that N-terminal fatty-acylation of Shh may play an important role in Shh-dependent signaling during rodent ventral forebrain formation.

Regionalization within the mammalian telencephalon is mediated by changes in responsiveness to Sonic Hedgehog

Development ◽  
1998 ◽  
Vol 125 (24) ◽  
pp. 5079-5089 ◽  
Author(s):  
J.D. Kohtz ◽  
D.P. Baker ◽  
G. Corte ◽  
G. Fishell
Keyword(s):  
Basal Ganglia ◽  
Globus Pallidus ◽  
Sonic Hedgehog ◽  
Adult Brain ◽  
Ganglionic Eminence ◽  
Lateral Ganglionic Eminence ◽  
Expression Characteristic ◽  
Sonic Hedgehog Gene ◽  
Embryonic Structure ◽  
Sequential Induction

The cortex and basal ganglia are the major structures of the adult brain derived from the embryonic telencephalon. Two morphologically distinct regions of the basal ganglia are evident within the mature ventral telencephalon, the globus pallidus medially, and the striatum, which is positioned between the globus pallidus and the cortex. Deletion of the Sonic Hedgehog gene in mice indicates that this secreted signaling molecule is vital for the generation of both these ventral telencephalic regions. Previous experiments showed that Sonic Hedgehog induces differentiation of ventral neurons characteristic of the medial ganglionic eminence, the embryonic structure which gives rise to the globus pallidus. In this paper, we show that later in development, Sonic Hedgehog induces ventral neurons with patterns of gene expression characteristic of the lateral ganglionic eminence. This is the embryonic structure from which the striatum is derived. These results suggest that temporally regulated changes in Sonic Hedgehog responsiveness are integral in the sequential induction of basal telencephalic structures.

The Gsh2 homeodomain gene controls multiple aspects of telencephalic development

Development ◽  
2000 ◽  
Vol 127 (23) ◽  
pp. 5007-5020 ◽  
Author(s):  
J.G. Corbin ◽  
N. Gaiano ◽  
R.P. Machold ◽  
A. Langston ◽  
G. Fishell
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Gabaergic Interneurons ◽  
Striatal Neurons ◽  
Ganglionic Eminence ◽  
Sonic Hedgehog Signaling ◽  
Early Loss ◽  
Downstream Target ◽  
Lateral Ganglionic Eminence ◽  
Development Proceeds

Homeobox genes have recently been demonstrated to be important for the proper patterning of the mammalian telencephalon. One of these genes is Gsh2, whose expression in the forebrain is restricted to the ventral domain. In this study, we demonstrate that Gsh2 is a downstream target of sonic hedgehog and that lack of Gsh2 results in profound defects in telencephalic development. Gsh2 mutants have a significant decrease in the expression of numerous genes that mark early development of the lateral ganglionic eminence, the striatal anlage. Accompanying this early loss of patterning genes is an initial expansion of dorsal telencephalic markers across the cortical-striatal boundary into the lateral ganglionic eminence. Interestingly, as development proceeds, there is compensation for this early loss of markers that is coincident with a molecular re-establishment of the cortical-striatal boundary. Despite this compensation, there is a defect in the development of distinct subpopulations of striatal neurons. Moreover, while our analysis suggests that the migration of the ventrally derived interneurons to the developing cerebral cortex is not significantly affected in Gsh2 mutants, there is a distinct delay in the appearance of GABAergic interneurons in the olfactory bulb. Taken together, our data support a model in which Gsh2, in response to sonic hedgehog signaling, plays a crucial role in multiple aspects of telencephalic development.

scholarly journals Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain

Development ◽  
2001 ◽  
Vol 128 (4) ◽  
pp. 527-540 ◽  
Author(s):  
S. Nery ◽  
H. Wichterle ◽  
G. Fishell
Keyword(s):  
Sonic Hedgehog ◽  
Retroviral Vectors ◽  
Medial Ganglionic Eminence ◽  
Wild Type ◽  
Ganglionic Eminence ◽  
Early Expression ◽  
Pdgfr Alpha

This study addresses the role of Sonic hedgehog (Shh) in promoting the generation of oligodendrocytes in the mouse telencephalon. We show that in the forebrain, expression of the early oligodendrocyte markers Olig2, plp/dm20 and PDGFR(alpha) corresponds to regions of Shh expression. To directly test if Shh can induce the development of oligodendrocytes within the telencephalon, we use retroviral vectors to ectopically express Shh within the mouse embryonic telencephalon. We find that infections with Shh-expressing retrovirus at embryonic day 9.5, result in ectopic Olig2 and PDGFR(alpha) expression by mid-embryogenesis. By postnatal day 21, cells expressing ectopic Shh overwhelmingly adopt an oligodendrocyte identity. To determine if the loss of telencephalic Shh correspondingly results in the loss of oligodendrocyte production, we studied Nkx2.1 mutant mice in which telencephalic expression of Shh is selectively lost. In accordance with Shh playing a role in oligodendrogenesis, within the medial ganglionic eminence of Nkx2.1 mutants, the early expression of PDGFR(alpha) is absent and the level of Olig2 expression is diminished in this region. In addition, in these same mutants, expression of both Shh and plp/dm20 is lost in the hypothalamus. Notably, in the prospective amygdala region where Shh expression persists in the Nkx2.1 mutant, the presence of plp/dm20 is unperturbed. Further supporting the idea that Shh is required for the in vivo establishment of early oligodendrocyte populations, expression of PDGFR(alpha) can be partially rescued by virally mediated expression of Shh in the Nkx2.1 mutant telencephalon. Interestingly, despite the apparent requirement for Shh for oligodendrocyte specification in vivo, all regions of either wild-type or Nkx2.1 mutant telencephalon are competent to produce oligodendrocytes in vitro. Furthermore, analysis of CNS tissue from Shh null animals definitively shows that, in vitro, Shh is not required for the generation of oligodendrocytes. We propose that oligodendrocyte specification is negatively regulated in vivo and that Shh generates oligodendrocytes by overcoming this inhibition. Furthermore, it appears that a Shh-independent pathway for generating oligodendrocytes exists.

Expression of zebrafish nk2.2 is influenced by sonic hedgehog/vertebrate hedgehog-1 and demarcates a zone of neuronal differentiation in the embryonic forebrain

Development ◽  
1995 ◽  
Vol 121 (6) ◽  
pp. 1755-1768 ◽  
Author(s):  
K.A. Barth ◽  
S.W. Wilson
Keyword(s):  
Neuronal Differentiation ◽  
Sonic Hedgehog ◽  
Narrow Band ◽  
Ectopic Expression ◽  
Homeobox Genes ◽  
Boundary Zone ◽  
Spatial Regulation ◽  
Signalling Molecule ◽  
The Brain

We have isolated zebrafish nk2.2, a member of the Nk-2 family of homeobox genes. nk2.2 is expressed in a continuous narrow band of cells along a boundary zone demarcating the location at which two of the earliest nuclei in the brain differentiate. This band of cells is located within a few cell diameters of cells expressing the signalling molecule sonic hedgehog/vertebrate hedgehog-1 (shh/vhh-1). Injection of shh/vhh-1 RNA results in ectopic expression of nk2.2 and concomitant abnormalities in the forebrain and eyes. Moreover, cyclops mutant embryos, which initially lack neurectodermal expression of shh/vhh-1, show a concomitant lack of nk2.2 expression. Together, these results suggest a requirement of shh/vhh-1 protein for the spatial regulation of nk2.2 expression.

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

scholarly journals Breeder Diet Strategies for Generating Ttpa-Null and Wild-Type Mice with Low Vitamin E Status to Assess Neurological Outcomes

2020 ◽  
Vol 4 (11) ◽  
Author(s):  
Katherine M Ranard ◽  
Matthew J Kuchan ◽  
John W Erdman
Keyword(s):  
Animal Model ◽  
Vitamin E ◽  
Mouse Model ◽  
Wild Type ◽  
Future Studies ◽  
Neurological Outcomes ◽  
Transfer Protein ◽  
And Function ◽  
The Brain ◽  
Vitamin E Status

ABSTRACT Studying vitamin E [α-tocopherol (α-T)] metabolism and function in the brain and other tissues requires an animal model with low α-T status, such as the transgenic α-T transfer protein (Ttpa)–null (Ttpa−/−) mouse model. Ttpa+/− dams can be used to produce Ttpa−/− and Ttpa+/+mice for these studies. However, the α-T content in Ttpa+/− dams’ diet requires optimization; diets must provide sufficient α-T for reproduction, while minimizing the transfer of α-T to the offspring destined for future studies that require low baseline α-T status. The goal of this work was to assess the effectiveness and feasibility of 2 breeding diet strategies on reproduction outcomes and offspring brain α-T concentrations. These findings will help standardize the breeding methodology used to generate the Ttpa−/− mice for neurological studies.

scholarly journals Analysis of maxillopedia Expression Pattern and Larval Cuticular Phenotype in Wild-Type and Mutant Tribolium

Genetics ◽  
2000 ◽  
Vol 155 (2) ◽  
pp. 721-731 ◽  
Author(s):  
Teresa D Shippy ◽  
Jianhua Guo ◽  
Susan J Brown ◽  
Richard W Beeman ◽  
Robin E Denell
Keyword(s):  
Rna Interference ◽  
Expression Pattern ◽  
Tribolium Castaneum ◽  
Expression Patterns ◽  
Ectopic Expression ◽  
Homeotic Gene ◽  
Wild Type ◽  
Double Stranded Rna ◽  
Similar Expression ◽  
Mutant Phenotypes

Abstract The Tribolium castaneum homeotic gene maxillopedia (mxp) is the ortholog of Drosophila proboscipedia (pb). Here we describe and classify available mxp alleles. Larvae lacking all mxp function die soon after hatching, exhibiting strong transformations of maxillary and labial palps to legs. Hypomorphic mxp alleles produce less severe transformations to leg. RNA interference with maxillopedia double-stranded RNA results in phenocopies of mxp mutant phenotypes ranging from partial to complete transformations. A number of gain-of-function (GOF) mxp alleles have been isolated based on transformations of adult antennae and/or legs toward palps. Finally, we have characterized the mxp expression pattern in wild-type and mutant embryos. In normal embryos, mxp is expressed in the maxillary and labial segments, whereas ectopic expression is observed in some GOF variants. Although mxp and Pb display very similar expression patterns, pb null embryos develop normally. The mxp mutant larval phenotype in Tribolium is consistent with the hypothesis that an ancestral pb-like gene had an embryonic function that was lost in the lineage leading to Drosophila.

scholarly journals BDNF haploinsufficiency induces behavioral endophenotypes of schizophrenia in male mice that are rescued by enriched environment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mahmoud Harb ◽  
Justina Jagusch ◽  
Archana Durairaja ◽  
Thomas Endres ◽  
Volkmar Leßmann ◽  
...  
Keyword(s):  
Prepulse Inhibition ◽  
Sensorimotor Gating ◽  
Enriched Environment ◽  
Fear Learning ◽  
Set Shifting ◽  
Wild Type ◽  
Mature Adult ◽  
Attentional Set ◽  
Attentional Set Shifting ◽  
The Brain

AbstractBrain-derived neurotrophic factor (BDNF) is implicated in a number of processes that are crucial for healthy functioning of the brain. Schizophrenia is associated with low BDNF levels in the brain and blood, however, not much is known about BDNF’s role in the different symptoms of schizophrenia. Here, we used BDNF-haploinsufficient (BDNF+/−) mice to investigate the role of BDNF in different mouse behavioral endophenotypes of schizophrenia. Furthermore, we assessed if an enriched environment can prevent the observed changes. In this study, male mature adult wild-type and BDNF+/− mice were tested in mouse paradigms for cognitive flexibility (attentional set shifting), sensorimotor gating (prepulse inhibition), and associative emotional learning (safety and fear conditioning). Before these tests, half of the mice had a 2-month exposure to an enriched environment, including running wheels. After the tests, BDNF brain levels were quantified. BDNF+/− mice had general deficits in the attentional set-shifting task, increased startle magnitudes, and prepulse inhibition deficits. Contextual fear learning was not affected but safety learning was absent. Enriched environment housing completely prevented the observed behavioral deficits in BDNF+/− mice. Notably, the behavioral performance of the mice was negatively correlated with BDNF protein levels. These novel findings strongly suggest that decreased BDNF levels are associated with several behavioral endophenotypes of schizophrenia. Furthermore, an enriched environment increases BDNF protein to wild-type levels and is thereby able to rescue these behavioral endophenotypes.

scholarly journals DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1

2019 ◽  
Vol 116 (50) ◽  
pp. 25322-25328 ◽  
Author(s):  
Yi Liu ◽  
Xiaopin Ma ◽  
Hisashi Fujioka ◽  
Jun Liu ◽  
Shengdi Chen ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Cellular Mechanism ◽  
Loss Of Function ◽  
Wild Type ◽  
Calcium Efflux ◽  
And Function ◽  
The Brain ◽  
Early Onset Parkinson’S Disease

Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.

Thymidine kinase-mediated killing of rat brain tumors

1993 ◽  
Vol 79 (5) ◽  
pp. 729-735 ◽  
Author(s):  
David Barba ◽  
Joseph Hardin ◽  
Jasodhara Ray ◽  
Fred H. Gage
Keyword(s):  
Gene Therapy ◽  
Brain Tumors ◽  
Tumor Cells ◽  
Wild Type ◽  
Cns Disorders ◽  
Content Type ◽  
Potential Applications ◽  
Ganciclovir Treatment ◽  
The Brain ◽  
Fine Print

✓ Gene therapy has many potential applications in central nervous system (CNS) disorders, including the selective killing of tumor cells in the brain. A rat brain tumor model was used to test the herpes simplex virus (HSV)-thymidine kinase (TK) gene for its ability to selectively kill C6 and 9L tumor cells in the brain following systemic administration of the nucleoside analog ganciclovir. The HSV-TK gene was introduced in vitro into tumor cells (C6-TK and 9L-TK), then these modified tumor cells were evaluated for their sensitivity to cell killing by ganciclovir. In a dose-response assay, both C6-TK and 9L-TK cells were 100 times more sensitive to killing by ganciclovir (median lethal dose: C6-TK, 0.1 µg ganciclovir/ml; C6, 5.0 µg ganciclovir/ml) than unmodified wild-type tumor cells or cultured fibroblasts. In vivo studies confirmed the ability of intraperitoneal ganciclovir administration to kill established brain tumors in rats as quantified by both stereological assessment of brain tumor volumes and studies of animal survival over 90 days. Rats with brain tumors established by intracerebral injection of wild-type or HSV-TK modified tumor cells or by a combination of wild-type and HSV-TK-modified cells were studied with and without ganciclovir treatments. Stereological methods determined that ganciclovir treatment eliminated tumors composed of HSV-TK-modified cells while control tumors grew as expected (p < 0.001). In survival studies, all 10 rats with 9L-TK tumors treated with ganciclovir survived 90 days while all untreated rats died within 25 days. Curiously, tumors composed of combinations of 9L and 9L-TK cells could be eliminated by ganciclovir treatments even when only one-half of the tumor cells carried the HSV-TK gene. While not completely understood, this additional tumor cell killing appears to be both tumor selective and local in nature. It is concluded that HSV-TK gene therapy with ganciclovir treatment does selectively kill tumor cells in the brain and has many potential applications in CNS disorders, including the treatment of cancer.

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