A molecular switch for the neuron-glia developmental decision.
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Animals↗
Biomedical subjects
D J Anderson
Publications and source records attributed to D J Anderson.
The cellular function of MASH1 in autonomic neurogenesis.
Using primary cultures and immortalized multipotential stem cell lines derived from wild-type and Mash1 mutant neural crest cells, we have analyzed the cellular function of MASH1 in autonomic neurogenesis. We present evidence for the existence of a precursor expressing MASH1 and neuronal markers such as neurofilament, neuron-specific tubulin, and tetanus toxin receptor. This cell has a nonneuronal morphology. Differentiation of this precursor to neurons that express markers such as SCG10, peripherin, and neuron-specific enolase is dependent upon MASH1 function. These data imply that the differentiation of autonomic neurons from uncommitted neural crest cells occurs in several sequential steps. Moreover, they suggest that MASH1 does not commit multipotent cells to a neural fate, like its Drosophila achaete-scute counterparts, but rather promotes the differentiation of a committed neuronal precursor.
Animals↗
Postmigratory neural crest cells expressing c-RET display restricted developmental and proliferative capacities.
c-RET is an orphan receptor tyrosine kinase essential for enteric neurogenesis in mice and is involved in several human genetic disorders. RET is also one of the earliest surface markers expressed by postmigratory neural crest cells in the gut. We generated anti-RET monoclonal antibodies to isolate such cells. We find that RET+ cells are antigenically and functionally distinct from neural crest stem cells (NCSCs) characterized previously. Unlike NCSCs, which are RET- and MASH1-, most RET+ cells express MASH1. Moreover, unlike NCSCs, which are multipotent and have high proliferative capacity, many RET+ cells generate only neurons following a limited number of divisions. This behavior is observed even in the presence of glial growth factor, a polypeptide that suppresses neuronal and promotes glial differentiation by NCSCs. These data provide direct evidence for the existence of committed neuronal progenitor cells and support a model of neural crest lineage diversification by progressive restriction of developmental potential.
Animals↗
Silencing is golden: negative regulation in the control of neuronal gene transcription.
Recent work has identified negative-acting DNA regulatory elements that function to prevent the expression of neuronal genes in non-neuronal cell types or in inappropriate neuronal subtypes. In some cases, the protein factors that interact with these silencer elements have been isolated and characterized. For example, the recently cloned silencer-binding factor NRSF/REST is a novel zinc-finger protein that interacts with silencer elements in a number of neuron-specific genes. These data suggest that negative regulation plays a major role in determining the diverse patterns of gene expression within the nervous system.
Animals↗
Should male infertility patients be tested for leukocytospermia?
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Humans↗
Genomic imprinting of Mash2, a mouse gene required for trophoblast development.
The mouse gene Mash2 encodes a transcription factor required for development of trophoblast progenitors. Mash2-homozygous mutant embryos die at 10 days postcoitum from placental failure. Here we show that Mash2 is genomically imprinted. First, Mash2+/- embryos inheriting a wild-type allele from their father die at the same stage as -/- embryos, with a similar placental phenotype. Second, the Mash2 paternal allele is initially expressed by groups of trophoblast cells at 6.5 and 7.5 days post-coitum, but appears almost completely repressed by 8.5 days post-coitum. Finally, we have genetically and physically mapped Mash2 to the distal region of chromosome 7, within a cluster of imprinted genes, including insulin-2, insulin-like growth factor-2 and H19.
Alleles↗
The packaging phenotype of the SE21Q1b provirus is related to high proviral expression and not trans-acting factors.
The avian packaging cell line SE21Q1b produces particles which encapsidate cellular RNAs. Such RNAs can be reverse transcribed by endogenous polymerase and integrated into the genomes of newly infected cells (M. Linial, Cell 49:93-102, 1987). Genomic RNA is not packaged because the packaging (psi) region of the provirus is deleted. The provirus also lacks the negative-strand primer binding site, which prevents efficient reverse transcription of randomly packaged genomic RNA. Previous work from our laboratory suggested that the trans-acting defect which allows packaging of cellular mRNA mapped to the provirus but did not map to the nucleocapsid region of the gag gene (D.J. Anderson, P. Lee, K. L. Levine, J. Sang, S. A. Shah, O. O. Yang, P. R. Shank, and M. L. Linial, J. Virol. 66:204-216, 1992). We have found, using proviral recombinants between SE21Q1b and wild-type Rous sarcoma virus, that packaging of cellular RNAs does not map to the gag gene. Rather, the propensity of SE21Q1b particles to package cellular mRNA is a function of the high level of particle production in these cells and not of any specific viral structural proteins.
Amino Acid Sequence↗
Differential regulation of transcription factor gene expression and phenotypic markers in developing sympathetic neurons.
We have examined the regulation of transcription factor gene expression and phenotypic markers in developing chick sympathetic neurons. Sympathetic progenitor cells first express the bHLH transcriptional regulator Cash-1 (a chicken achaete-scute homologue), followed by coordinate expression of Phox2, a paired homeodomain protein, and GATA-2, a zinc finger protein. SCG10, a pan-neuronal membrane protein, is first detected one stage later, followed by the catecholaminergic neurotransmitter enzyme tyrosine hydroxylase (TH). We have used these markers to ask two questions: (1) is their expression dependent upon inductive signals derived from the notochord or floor plate?; (2) does their sequential expression reflect a single linear pathway or multiple parallel pathways? Notochord ablation experiments indicate that the floor plate is essential for induction of GATA-2, Phox2 and TH, but not for that of Cash-1 and SCG10. Taken together these data suggest that the development of sympathetic neurons involves multiple transcriptional regulatory cascades: one, dependent upon notochord or floor plate-derived signals and involving Phox2 and GATA-2, is assigned to the expression of the neurotransmitter phenotype; the other, independent of such signals and involving Cash-1, is assigned to the expression of pan-neuronal properties. The parallel specification of different components of the terminal neuronal phenotype is likely to be a general feature of neuronal development.
Animals↗
The acetabular response to proximal femoral varus rotational osteotomy. Results after failure of post-reduction abduction splinting in patients who had congenital dislocation of the hip.
The acetabular response to proximal femoral varus rotational osteotomy was studied radiographically in twenty-eight patients who had had thirty-three congenitally dislocated hips. All of the patients had previously been managed with open or closed reduction followed by use of a spica cast and had worn an abduction orthosis for at least one year after the reduction. The indications for the femoral osteotomy were a persistently increased acetabular index or subluxation, or both. The average of the patients at the time of the femoral osteotomy was twenty-five months. The average preoperative acetabular index was 32 degrees. At an average of seven years after the osteotomy, the acetabular index had improved to an average of 16 degrees. Four hips had had one subsequent procedure for persistent acetabular dysplasia. Despite a failure of the acetabulum to respond to use of an abduction splint, the proximal femoral varus rotational osteotomy stimulated improvement in the acetabular index to within normal limits in twenty-nine of the thirty-three hips.
Acetabulum↗
Cholinergic channel activators: novel opportunities for the treatment of CNS disorders.
Negative connotations associated with the use of (-)-nicotine has limited medicinal chemistry research in the area of nAChRs [5]. However, recent evidence suggests that a diversity of nAChR subunits exist, that each subtype may be involved in mediating specific neurochemical/behaviors, and that these subtypes have a defined pharmacology that may be selectively targeted [1]. (+/-)-Epibatidine, GTS-21 and ABT-418 differentially interact with nAChR subtypes to elicit a diversity of behavioral effects including analgesia, neuroprotection and cognitive enhancement. These agents therefore represent important new pharmacological probes to dissect the nAChR subtype(s) mediating specific pharmacological responses to nAChR activation.
Animals↗
Immunobiology of the human penile urethra.
The human penile urethra contains numerous IgA and J chain-positive plasma cells, and the epithelium expresses secretory component, the transport molecule for polymeric IgA, indicating that this region is an active site of secretory IgA-mediated immune defense. At the distal tip, the mucosae of the meatus and fossa navicularis contain intraepithelial dendritic cells but few macrophages, whereas the urethra proper contains many macrophages within the lamina propria and epithelium, but no dendritic cells. T lymphocytes are abundant and ubiquitous in all regions of the urethra. Both CD8+ and CD4+ subpopulations of T lymphocytes are present in the lamina propria and epithelium, although CD8+ cells predominate. The majority of T lymphocytes are positive for CD45RO (memory marker), and many are also positive for the alpha E beta 7 integrin (mucosal-associated antigen). These data indicate that the human urethra is a highly dynamic immunocompetent tissue possessing all the necessary elements for antigen presentation and both humoral and cellular mucosal immune responses. Furthermore, the urethra resembles other mucosal surfaces in terms of lymphocyte subpopulations, segregation of phenotypes and expression of antigenic determinants characteristic of mucosal lymphocytes. It is likely that this region plays a dominant role in protecting the male urogenital tract against ascending infections, and should be targeted in vaccination strategies directed against sexually transmitted diseases.
Adult↗
Characterization of [3H]ABT-418: a novel cholinergic channel ligand.
ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole] is a potent and selective agonist at neuronal nicotinic acetylcholine receptors (nAChRs) with cognitive enhancing and anxiolytic activities. [3H]ABT-418 was found to bind with high affinity (KD = 2.85 +/- 0.14 nM) to membranes prepared from rat brain. Binding of [3H]ABT-418 was characterized by rapid association (T1/2 = 1.4 +/- 0.3 min) and dissociation (T1/2 = 2.9 +/- 0.4 min) half-times. The pharmacology of [3H]ABT-418 binding was consistent with an interaction with the putative alpha 4 beta 2 nAChR subtype. The nAChR agonists, (-)-nicotine, (-)-cytisine and (+/-)-epibatidine, displayed a high affinity (Ki = 0.8 +/- 0.1, 0.2 +/- 0.1 and 0.05 +/- 0.01 nM, respectively) for [3H]ABT-418 binding sites, whereas among nAChR antagonists examined, only dihydro-beta-erythroidine competed with high affinity (Ki = 32 +/- 1.5 nM). Although autoradiography studies indicate that the binding distribution of [3H]ABT-418 and (-)-[3H]cytisine are largely identical, there are some brain regions including the striatum, olivary pretectal nucleus and the superior colliculus, in which [3H]ABT-418 demonstrates significantly (P < .05) less binding. The data in the present study demonstrate that [3H]ABT-418 binds with high affinity to a population of binding sites in the rat brain that have the pharmacological characteristics of neuronal nAChRs. [3H]ABT-418 may, therefore, serve as a useful radioligand to further probe the observed differences in pharmacological properties between ABT-418 and other nicotinic agonists in vivo.
Alkaloids↗
Antibiotic therapy and leukocytospermia: a prospective, randomized, controlled study.
OBJECTIVE: To determine the efficacy of common antibiotic therapies for treatment of leukocytospermia of unknown etiology. DESIGN: Prospective, randomized, controlled clinical study. SETTING: Fertility and Endocrinology Unit at Brigham and Women's Hospital, Boston, Massachusetts. PATIENTS: One thousand seven hundred ten male partners in infertile couples attending the Fertility and Endocrinology Unit. INTERVENTIONS: Concentrations of seminal peroxidase-positive granulocytes were determined during all routine semen analyses performed over a 30-month period. Of 119 men found to have leukocytospermia (> 10(6) granulocytes/mL semen) on first visit, 54 agreed to be randomized into one of three groups, and 41 patients completed the study. Group I (n = 13) and their wives received a 14-day course of oral doxycycline, 100 mg twice per day. Group II (n = 11) and their wives received a 14-day course of oral trimethoprim 160 mg-sulfamethoxazole 800 mg twice per day. Group III (n = 17) and their wives received no therapy. Four weeks after randomization, repeat semen analyses and granulocyte quantitations were done. RESULTS: Neither of the antibiotic regimens resulted in a significantly higher rate of resolution of leukocytospermia over that seen in the control group. CONCLUSIONS: There is a high rate of spontaneous resolution of leukocytospermia after one positive test. Antibiotics are no more beneficial than no therapy for treatment of this condition.
Adult↗
Heterosexual HIV transmission.
Most of the people now living with HIV acquired the infection through heterosexual intercourse. HIV transmission has been facilitated by (a) concomitant sexually transmitted diseases (STDs), (b) the presence of social conditions that create core groups who have frequent and numerous partners, (c) sexual practices associated with bleeding (i.e., trauma, sex during menses) as well as noncircumcision, (d) cervical ectopy, and (e) anal sex. HIV may be found both cell-free and as intracellular virus in genital tract secretion, and may be sexually transmitted through either mechanism. HIV titers in genital tract secretions vary by several logs between people and within individuals over time, being greatest just after seroconversion and with advanced immunosuppression, concomitant genital tract inflammation (including STDs), and decreasing (but not to zero) with antiretroviral therapy. The per-contact transmission efficiency rate is highly variable, ranging from > 3% to < 1 per thousand contacts, with male-to-female HIV transmission generally being more efficient than vice versa. Control of the heterosexual HIV epidemic will necessitate a multidisciplinary approach, utilizing direct biological approaches (e.g., culturally specific and behavioral interventions, as well as more fundamental community changes that decrease societal norms that augment unsafe practices.
Cervix Mucus↗
Ligands for brain cholinergic channel receptors: synthesis and in vitro characterization of novel isoxazoles and isothiazoles as bioisosteric replacements for the pyridine ring in nicotine.
Ligands which activate neuronal nicotinic acetylcholine receptors (nAChRs) represent a potential approach for the palliative treatment for the symptoms of memory loss associated with Alzheimer's disease (AD). Based upon this approach, a series of novel 3,5-disubstituted isoxazoles and isothiazoles were prepared and evaluated in vitro as cholinergic channel activators (ChCAs) of neuronal nAChRs. Many of the 3-substituted 5-(2-pyrrolidinyl)isoxazoles were found to have nanomolar binding affinities comparable to (S)-nicotine (2a) in a preparation of whole rat brain. However, in a paradigm measuring the evoked release of [3H]dopamine from a preparation of rat striatum, there were differences in the agonist potencies and efficacies of these analogues relative to 2a. The differences in agonist potency observed between compounds of comparable binding potency may be due to differences in ligand interactions with various subtypes of neuronal nAChRs.
Animals↗
Synthesis and evaluation of nicotine analogs as neuronal nicotinic acetylcholine receptor ligands.
A series of 3'-, 4'-, and 5'-substituted nicotine analogs have been synthesized and evaluated as ligands of the neuronal nicotinic acetylcholine receptor. The compounds prepared were found to have binding affinities ranging from 4 to 3500 nM. The results indicate that only a small substituent or functionality is well tolerated at the C4' position of nicotine and that binding affinity is affected by both steric and electronic properties of the substituent. On the other hand, the C3' and C5' positions seem to be the more sensitive toward bulky substituents. The best compound, 4'-methylnicotine, is nearly equipotent to nicotine. It possesses the most favorable binding affinity.
Ligands↗
Glial growth factor restricts mammalian neural crest stem cells to a glial fate.
Growth factors and cytokines are thought to influence the development of uncommitted progenitor cell populations, but the issue of how these factors act on individual cells remains controversial. Such factors may act simply as selective mitogens or survival factors for cells that undergo lineage restrictions stochastically. Alternatively, they may instruct or bias multipotent cells to choose one lineage at the expense of others. Here we show that glial growth factor (GGF), previously defined as a Schwann cell mitogen, strongly suppresses neuronal differentiation of rat neural crest stem cells while promoting or allowing glial differentiation. Quantitative clonal analysis suggests that the action of GGF is likely to be instructive rather than selective. Taken together with the expression pattern of GGF, these data suggest a lateral signaling model for the diversification of cell types within developing peripheral ganglia.
Animals↗
Expression of trk in MAH cells lacking the p75 low-affinity nerve growth factor receptor is sufficient to permit nerve growth factor-induced differentiation to postmitotic neurons.
We have transfected MAH cells, an immortalized sympathoadrenal progenitor cell line, with a plasmid encoding the 140-kDa Trk protein, a nerve growth factor (NGF) receptor with protein-tyrosine kinase activity. NGF promotes neurite outgrowth and proliferation from such cells, indicating that Trk is sufficient to mediate such responses in the absence of significant levels of the endogenous 75-kDa low-affinity NGF receptor (p75). These initial NGF responses are indistinguishable from those evoked by basic fibroblast growth factor (bFGF). However, NGF is sufficient to promote terminal differentiation of a approximately 8% of trk-transfected MAH cells to postmitotic, NGF-dependent neurons, whereas all cells eventually die in medium with bFGF. Other environmental signals (such as depolarization or ciliary neurotrophic factor) can cooperate with NGF to enhance production of postmitotic NGF-dependent neurons in trk-transfected MAH cells. The terminal differentiation of sympathetic neurons thus involves sequential and cooperative actions of different growth and neurotrophic factors, as well as cell-intrinsic changes in the response to these factors.
Animals↗