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PubMed2005

Is hypertension a disorder of volume control? What is the evidence?

The etiological factors responsible for the hypertensive phenotype are complex and several experimental and clinical observations point to a major role of the kidney as being responsible. Genetic studies of uncommon diseases which express monogenetic inheritance all have in common a dysregulation of Na+ balance and volume expansion. Furthermore, epidemiological data suggest an increased incidence of hypertension in communities with high excretory rates of Na+. Experimental data also suggest that low birth weight is associated with an increase in the frequency of hypertension later in life and raises the possibility that intrauterine imprinting may contribute to the expression of the phenotype. Upregulation of the Na+/K+/2Cl- and thiazide-sensitive transporters in low birth weight animals may provide the physiological basis for these observations. In addition, low birth weight is associated with a decrease in nephron number. Therefore, low nephron number may induce adaptive changes in utero which influence volume homeostasis later in life and subtle gain of function mutations in one or more of these transporters may unmask defects in volume homeostasis with increasing salt intake. Finally, the high prevalence of hypertension in functionally anephric patience seems to respond to sustained maintenance of 'dry weight' through ultrafiltration.

Animals↗
PubMed2003

Thrombospondin-4 and its variants: expression and differential effects on endothelial cells.

BACKGROUND: In a recent large-scale genetic association study, a single nucleotide polymorphism in the thrombospondin-4 (TSP-4) gene, resulting in a proline-for-alanine substitution at position 387, was associated with a significantly increased risk for premature atherosclerosis. TSP-4 had not previously been implicated in vascular pathology, and very little information is available on its expression and functions. METHODS AND RESULTS: The goal of this study was to assess TSP-4 expression in vessel wall and to identify differences in functions of TSP-4 variants that could account for the proatherogenic effects of the (P387)TSP-4 variant. TSP-4 expression was demonstrated in human endothelial cells (ECs) and vascular smooth muscle cells from brain blood vessels and coronary arteries. (P387)TSP-4 and its fragment (residues 326 to 722), but not the A(387) forms, suppressed EC adhesion and proliferation. The (P387)TSP-4 was more active in inducing the phosphorylation of focal adhesion kinase, consistent with inhibition of proliferation. Both variant fragments increased the proliferation of human aortic smooth muscle cells. CONCLUSIONS: TSP-4 is expressed by vascular cells and influences the vessel wall by modulating the proliferation of ECs and smooth muscle cells. The A387P substitution is a "gain-of-function" mutation, favoring a form of TSP-4 that interferes with EC adhesion and proliferation and may thereby be proatherogenic.

Arteriosclerosis↗
PubMed2004

Amplified transmural dispersion of repolarization as the basis for arrhythmogenesis in a canine ventricular-wedge model of short-QT syndrome.

BACKGROUND: The short-QT syndrome is a new clinical entity characterized by corrected QT intervals <300 ms and a high incidence of ventricular tachycardia (VT) and fibrillation (VF). Gain-of-function mutations in the gene for outward potassium currents have been shown to underlie the congenital syndrome. The present study examined the cellular basis of VT/VF in an experimental model associated with short QT intervals created with a potassium channel activator. METHODS AND RESULTS: Transmembrane action potentials from epicardial and M regions, 4 transmural unipolar electrograms, and a pseudo-ECG were simultaneously recorded in canine arterially perfused left ventricular wedge preparations. At a basic cycle length of 2000 ms, pinacidil (2 to 3 mumol/L) abbreviated the QT interval from 303.7+/-5.4 to 247.3+/-6.9 ms (mean+/-SEM, P<0.0001). The maximal transmural dispersion of repolarization (TDR(max)) increased from 27.0+/-3.8 to 64.9+/-9.2 ms (P<0.01), and an S2 applied to the endocardium induced a polymorphic VT (pVT) in 9 of 12 wedge preparations (P<0.01). Addition of isoproterenol (100 nmol/L, n=5) led to greater abbreviation of the QT interval, a further increase in TDR(max) (from 55.4+/-13.7 to 69.7+/-8.3 ms), and more enduring pVT. TDR(max) was correlated significantly with the T(peak)-T(end) interval under all conditions. The effects of pinacidil were completely reversed by glybenclamide (10 micromol/L, n=4) and partially reversed by E4031 (5 micromol/L, n=5), which prevented induction of pVT in 3 of 5 preparations. CONCLUSIONS: Our data suggest that heterogeneous abbreviation of the action potential duration among different cell types spanning the ventricular wall creates the substrate for the genesis of VT under conditions associated with short QT intervals.

Action Potentials↗
PubMed2006

Epithelial sodium channel allele T594M is not associated with blood pressure or blood pressure response to amiloride.

The T594M allele of the epithelial sodium channel beta-subunit has been proposed as a gain-of-function mutation leading to salt-sensitive hypertension in blacks that is particularly responsive to the specific sodium channel antagonist amiloride. However, the positive associations derive from small convenience samples, and the amiloride challenge study lacked a control group. We determined whether the T594M allele was associated with hypertension and blood pressure (BP) response to amiloride in 2 well-characterized random population samples including 3137 Dallas County subjects and 1666 Jamaican blacks. In multivariate models, the T594M allele was not predictive of systolic BP (adjusted odds ratio for hypertension 1.1; 95% confidence interval, 0.7 to 1.8). Amiloride treatment did not lower the BP of 6 T594M heterozygotes significantly more than in 22 control subjects (P=0.8). We conclude that the T594M allele does not contribute significantly to BP in blacks and does not predict a significantly superior response to amiloride therapy.

Adult↗
PubMed2026

Mice humanized by syntenic replacement with full-length NLRP3 disease-associated variants model the clinical cryopyrinopathy continuum.

Next-generation sequencing technologies are increasingly used to diagnose genetic disorders, particularly immunological diseases with broad and overlapping immune dysregulation. Cryopyrin-associated periodic syndromes (CAPS) are caused by gain-of-function mutations in NLRP3 and include 3 autoinflammatory diseases spanning a continuum of severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Linking NLRP3 variants to protein dysfunction and clinical phenotype remains challenging because of genetic modifiers and environmental factors. We report the generation and phenotyping of 5 mouse lines expressing either the common human NLRP3 allele or 1 of 4 CAPS mutations spanning the disease spectrum from FCAS to NOMID. In these lines, the murine Nlrp3 locus is replaced by syntenic integration of the human NLRP3 locus, yielding 1 line with the common allele and 4 lines each carrying a distinct CAPS mutation. Unlike models in which a human mutation is introduced into the mouse protein, these lines recapitulate the spectrum of disease severity observed in humans. These findings support a model in which evaluation of nonsynonymous mutations in mice is optimized when introduced in the context of the human gene. This suggests that species-specific regulation and/or intramolecular epistasis may impact modeling of disease-associated variants.

Animals↗
PubMed2006

Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era.

JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, occurs in nearly all patients with polycythemia vera (PV) but also in a variable proportion of patients with other myeloid disorders; mutational frequency is estimated at approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF), up to 20% in certain subcategories of atypical myeloproliferative disorder (atypical MPD), less than 3% in de novo myelodysplastic syndrome (MDS) or acute myeloid leukemia, and 0% in chronic myeloid leukemia (CML). Accordingly, there is now molecular justification for grouping PV, ET, and MF together in a distinct MPD category (i.e., classic, BCR-ABL(-) MPD) that is separate from chronic myeloid leukemia (CML), MDS, and atypical MPD. To date, JAK2V617F has not been described in patients with reactive myeloproliferation, lymphoid disorders, or solid tumor. Therefore, the presence of JAK2V617F strongly suggests an underlying MPD and it is therefore reasonable to consider JAK2V617F-based laboratory tests for the evaluation of polycythemia, primary thrombocytosis, unexplained leukocytosis, bone marrow fibrosis, or abdominal vein thrombosis. Current information on disease-specific prognostic relevance of JAK2V617F is inconclusive and confounded by inter-study differences in the performance of mutation screening assays. Regardless, the discovery of JAK2V617F has reinforced the pathogenetic contribution of JAK-STAT signaling in MPD and identifies JAK2 as a valid drug target.

Disease Management↗
PubMed2006

PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase.

Elucidation of the molecular mechanisms underlying carcinogenesis has benefited tremendously from the identification and characterization of oncogenes and tumor suppressor genes. One new advance in this field is the identification of PTPN11 as the first proto-oncogene that encodes a cytoplasmic tyrosine phosphatase with 2 Src-homology 2 (SH2) domains (Shp2). This tyrosine phosphatase was previously shown to play an essential role in normal hematopoiesis. More recently, somatic missense PTPN11 gain-of-function mutations have been detected in leukemias and rarely in solid tumors, and have been found to induce aberrant hyperactivation of the Ras-Erk pathway. This progress represents another milestone in the leukemia/cancer research field and provides a fresh view on the molecular mechanisms underlying cell transformation.

Hematopoiesis↗
PubMed2006

Orientation of endothelial cell division is regulated by VEGF signaling during blood vessel formation.

New blood vessel formation requires the coordination of endothelial cell division and the morphogenetic movements of vessel expansion, but it is not known how this integration occurs. Here, we show that endothelial cells regulate division orientation during the earliest stages of blood vessel formation, in response to morphogenetic cues. In embryonic stem (ES) cell-derived vessels that do not experience flow, the plane of endothelial cytokinesis was oriented perpendicular to the vessel long axis. We also demonstrated regulated cleavage orientation in vivo, in flow-exposed forming retinal vessels. Daughter nuclei moved away from the cleavage plane after division, suggesting that regulation of endothelial division orientation effectively extends vessel length in these developing vascular beds. A gain-of-function mutation in VEGF signaling increased randomization of endothelial division orientation, and this effect was rescued by a transgene, indicating that regulation of division orientation is a novel mechanism whereby VEGF signaling affects vessel morphogenesis. Thus, our findings show that endothelial cell division and morphogenesis are integrated in developing vessels by flow-independent mechanisms that involve VEGF signaling, and this cross talk is likely to be critical to proper vessel morphogenesis.

Animals↗
PubMed2005

Silencing of the mutant SCAP allele accounts for restoration of a normal phenotype in CT60 cells selected for NPC1 expression.

The sterol regulatory element binding protein (SREBP)/SREBP cleavage-activating protein (SCAP) complex regulates the transcription of numerous genes involved in cellular cholesterol metabolism. The CHO mutant, CT60, and its parental cell line, 25RA, possess a gain-of-function mutation in one allele of the SCAP gene that renders the cells resistant to sterol-mediated suppression of cholesterol synthesis and uptake. In addition, CT60 cells do not express a functional Niemann-Pick type C1 (NPC1) protein, which leads to lysosomal accumulation of free cholesterol. Correction of the NPC1 defect by expression of a yeast artificial chromosome (YAC) containing the NPC1 genetic interval restored normal mobilization of cholesterol from the lysosomal compartment. Unexpectedly, the YAC-containing cell lines have overall cellular cholesterol concentrations that are comparable to wild-type levels, despite the assumed presence of the SCAP mutation. This phenotypic change results from a reduction in endogenous sterol synthesis, LDL receptor message, and HMG-CoA reductase message. Genetic analysis of the SCAP gene revealed that the YAC-expressing CT60 cells have normal regulation of these sentinel cholesterogenic genes as a result of selective silencing of the mutant SCAP allele, which appears to be independent of functional NPC1 expression.

Animals↗
PubMed2001

Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients.

Hyperinsulinism and hyperammonemia syndrome has been reported as a cause of moderately severe hyperinsulinism with diffuse involvement of the pancreas. The disorder is caused by gain of function mutations in the GLUD1 gene, resulting in a decreased inhibitory effect of guanosine triphosphate on the glutamate dehydrogenase (GDH) enzyme. Twelve unrelated patients (six males, six females) with hyperinsulinism and hyperammonemia syndrome have been investigated. The phenotypes were clinically heterogeneous, with neonatal and infancy-onset hypoglycemia and variable responsiveness to medical (diazoxide) and dietary (leucine-restricted diet) treatment. Hyperammonemia (90-200 micromol/L, normal <50 micromol/L) was constant and not influenced by oral protein, by protein- and leucine-restricted diet, or by sodium benzoate or N-carbamylglutamate administration. The patients had mean basal GDH activity (18.3 +/- 0.9 nmol/min/mg protein) not different from controls (17.9 +/- 1.8 nmol/min/mg protein) in cultured lymphoblasts. The sensitivity of GDH activity to inhibition by guanosine triphosphate was reduced in all patient lymphoblast cultures (IC(50), or concentrations required for 50% inhibition of GDH activity, ranging from 140 to 580 nM, compared with control IC(50) value of 83 +/- 1.0 nmol/L). The allosteric effect of ADP was within the normal range. The activating effect of leucine on GDH activity varied among the patients, with a significant decrease of sensitivity that was correlated with the negative clinical response to a leucine-restricted diet in plasma glucose levels in four patients. Molecular studies were performed in 11 patients. Heterozygous mutations were localized in the antenna region (four patients in exon 11, two patients in exon 12) as well as in the guanosine triphosphate binding site (two patients in exon 6, two patients in exon 7) of the GLUD1 gene. No mutation has been found in one patient after sequencing the exons 5-13 of the gene.

Adolescent↗
PubMed1996

The calcium-sensing receptor: a window into the physiology and pathophysiology of mineral ion metabolism.

The recent cloning of a [Ca2+]o-sensing receptor from several different tissues in several species directly demonstrates that a variety of cells can directly recognize and respond to small changes in their ambient level of [Ca2+]o through a G protein-coupled, cell surface receptor. This finding directly documents that [Ca2+]o can act as an extracellular, first messenger in addition to subserving its better known role as an intracellular second messenger. Several of the tissues expressing the CaR are important elements in the calcium homeostatic system that have long been known to be capable of sensing [Ca2+]o, such as parathyroid and thyroidal C cells. The presence of the receptor in the kidney, however, provides strong evidence that several of the long-recognized but poorly understood direct actions of [Ca2+]o on renal function could be mediated by the CaR. These actions include the up-regulation of urinary calcium and magnesium excretion in the setting of hypercalcemia, which complements the indirect inhibition of renal tubular reabsorption of calcium that results from high [Ca2+]o-mediated inhibition for PTH secretion. The impaired renal concentrating capacity in hypercalcemia is likely a manifestation of a homeostatically important interaction between the regulation of renal calcium and water handling that reduces the risk of pathological deposition of calcium in the kidney when there is a need to dispose of excess, calcium in the urine. In this regard, the availability of human syndromes of [Ca2+]o "resistance" or "overresponsiveness" due to loss-of-function or gain-of-function mutations in the CaR, respectively, have provided useful experiments in nature that have clarified the importance of the receptor in both abnormal and normal physiology. Much remains to be learned, however, about the role of the CaR in locations, such as the brain, where it likely responds to local rather than systemic levels of [Ca2+]o. In such sites, it may represent an important modulator of neuronal function, responding to [Ca2+]o as a neuromodulator or even neurotransmitter. The development of therapeutics that either activate or inhibit the function of the CaR may be useful for treating a variety of conditions in which the receptor is either under- or overactive. Finally, it would not be surprising to discover additional receptors for [Ca2+]o or for other ions (the CaR may, in fact, be an important [Mg2+]o-sensor) that could function abnormally in certain disease states and be amenable to pharmacological manipulation with ion receptor-based therapeutics.

Animals↗
PubMed2002

The epithelial Na+ channel: cell surface insertion and retrieval in Na+ homeostasis and hypertension.

The epithelial Na+ channel (ENaC) forms the pathway for Na+ absorption in the kidney collecting duct and other epithelia. Dominant gain-of-function mutations cause Liddle's syndrome, an inherited form of hypertension resulting from excessive renal Na+ absorption. Conversely, loss-of-function mutations cause pseudohypoaldosteronism type I, a disorder of salt wasting and hypotension. Thus, ENaC has a critical role in the maintenance of Na+ homeostasis and blood pressure control. Altered Na+ absorption in the lung may also contribute to the pathogenesis of cystic fibrosis. Epithelial Na+ absorption is regulated in large part by mechanisms that control the expression of ENaC at the cell surface. Nedd4, a ubiquitin protein ligase, binds to ENaC and targets the channel for endocytosis and degradation. Liddle's syndrome mutations disrupt the interaction between ENaC and Nedd4, resulting in an increase in the number of ENaC channels at the cell surface. Aldosterone and vasopressin also regulate Na+ absorption to defend against hypotension and hypovolemia. Both hormones increase the expression of ENaC at the cell surface. The goal of this review is to summarize recent data on the regulation of ENaC expression at the cell surface.

Animals↗
PubMed1996

Role of the RET proto-oncogene in sporadic hyperparathyroidism and in hyperparathyroidism of multiple endocrine neoplasia type 2.

Parathyroid tumors occur either sporadically or as part of inherited syndromes such as multiple endocrine neoplasia (MEN) types 2A and 2B. The development of both of these familial syndromes has been related to specific germline gain-of-function mutations predominantly in exons 10 and 11 (MEN 2A) and 16 (MEN 2B) of the RET proto-oncogene. The same mutations have also been implicated in the pathogenesis of sporadic medullary thyroid carcinoma and sporadic pheochromocytoma. The RET mutations are thought to have a transforming effect only in cells of neural crest origin such as thyroid parafollicular (C-cells) and adrenal chromaffin cells, which normally express the RET proto-oncogene. Expression of RET messenger RNA has not yet been studied in the parathyroid, however, we demonstrate in this study by a sensitive, semiquantitative RT-PCR technique and in situ hybridization, that RET is expressed in MEN 2A parathyroid tumors and in sporadic adenomas. Although DNA from a parathyroid tumor of a MEN 2A patient displayed an expected mutation, none of the previously described MEN 2A or 2B mutations were found in DNA of 34 sporadic adenomas. Our data suggest that parathyroid disease is an integral part of the MEN 2A syndrome, but that MEN 2 mutations in RET rarely play a part in the pathogenesis of sporadic parathyroid tumors.

Adenoma↗
PubMed2000

Enzymatic activities of P450c17 stably expressed in fibroblasts from patients with the polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting approximately 5-10% of women of reproductive age. The clinical features of PCOS include oligo/anovulation, hyperandrogenemia, and hyperinsulinemia. Because P450c17 is the single enzyme catalyzing both 17alpha-hydroxylase and 17,20-lyase activities in the ovary and adrenal, some have suggested that defects in P450c17 may cause the hyperandrogenism of PCOS. Previous studies have shown that serine hyperphosphorylation of P450c17 increases the enzyme's 17,20-lyase activity, thereby favoring androgen production, and that serine phosphorylation of the insulin receptor beta-chain (IR-beta) inhibits IR-beta tyrosine phosphorylation, causing insulin resistance in vitro. We previously suggested that a gain of function mutation in a single serine kinase might cause the hyperandrogenism and insulin resistance observed in PCOS patients by excessive phosphorylation of both P450c17 and IR-beta. To test this hypothesis, we obtained fibroblasts from nine previously studied patients: three controls, three PCOS patients with normal levels of IR-beta serine phosphorylation, and three PCOS patients with increased levels of IR-beta serine phosphorylation. Initial studies showed that such skin fibroblasts could not be transfected effectively by calcium phosphate, diethylaminoethyl-dextran, lipofection or adenovirus procedures. Therefore, we employed a retroviral infection system to stably express human P450c17 in the primary cultures of fibroblast cells from the PCOS patients and controls and measured the resulting 17alpha-hydroxylase and 17,20-lyase activity. The cells were analyzed in a blinded fashion until the study was complete. The 17alpha-hydroxylase and 17,20-lyase activities in each cell line correlated well with the amount of P450c17 protein expressed, but there was no correlation between either enzymatic activity (or their ratio) with the clinical phenotype of the cells' donors even when results were corrected for the number of P450c17 complementary DNA inserts per cell line. Overnight incubation with 1 micromol/L insulin also did not affect enzymatic activity. Thus, we were unable to find evidence for the hypothesis that in PCOS a single abnormal kinase hyperphosphorylates both IR-beta, causing insulin resistance, and P450c17, causing hyperandrogenism. However, because fibroblasts do not normally express either P450c17 or the accessory proteins needed for its optimal activity, these results cannot exclude a role for serine phosphorylation in the hyperandrogenism and insulin resistance of PCOS.

Adolescent↗
PubMed2000

The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7.

Glycoprotein hormone receptors, including LH receptor, FSH receptor, and TSH receptor, belong to the large G protein-coupled receptor (GPCR) superfamily but are unique in having a large ectodomain important for ligand binding. In addition to two recently isolated mammalian LGRs (leucine-rich repeat-containing, G protein-coupled receptors), LGR4 and LGR5, we further identified two new paralogs, LGR6 and LGR7, for glycoprotein hormone receptors. Phylogenetic analysis showed that there are three LGR subgroups: the known glycoprotein hormone receptors; LGR4 to 6; and a third subgroup represented by LGR7. LGR6 has a subgroup-specific hinge region after leucine-rich repeats whereas LGR7, like snail LGR, contains a low density lipoprotein (LDL) receptor cysteine-rich motif at the N terminus. Similar to LGR4 and LGR5, LGR6 and LGR7 mRNAs are expressed in multiple tissues. Although the putative ligands for LGR6 and LGR7 are unknown, studies on single amino acid mutants of LGR7, with a design based on known LH and TSH receptor gain-of-function mutations, indicated that the action of LGR7 is likely mediated by the protein kinase A but not the phospholipase C pathway. Thus, mutagenesis of conserved residues to allow constitutive receptor activation is a novel approach for the characterization of signaling pathways of selective orphan GPCRs. The present study also defines the existence of three subclasses of leucine-rich repeat-containing, G protein-coupled receptors in the human genome and allows future studies on the physiological importance of this expanding subgroup of GPCR.

Amino Acid Sequence↗
PubMed2004

Overlapping and non-redundant functions of the Arabidopsis auxin response factors MONOPTEROS and NONPHOTOTROPIC HYPOCOTYL 4.

Transcription factors of the auxin response factor (ARF) family have been implicated in auxin-dependent gene regulation, but little is known about the functions of individual ARFs in plants. Here, interaction assays, expression studies and combinations of multiple loss- and gain-of-function mutants were used to assess the roles of two ARFs, NONPHOTOTROPIC HYPOCOTYL 4 (NPH4/ARF7) and MONOPTEROS (MP/ARF5), in Arabidopsis development. Both MP and NPH4 interact strongly and selectively with themselves and with each other, and are expressed in vastly overlapping domains. We show that the regulatory properties of both genes are far more related than suggested by their single mutant phenotypes. NPH4 and MP are capable of controlling both axis formation in the embryo and auxin-dependent cell expansion. Interaction of MP and NPH4 in Arabidopsis plants is indicated by their joint requirement in a number of auxin responses and by synergistic effects associated with the co-overexpression of both genes. Finally, we demonstrate antagonistic interaction between ARF and Aux/IAA gene functions in Arabidopsis development. Overexpression of MP suppresses numerous defects associated with a gain-of-function mutation in BODENLOS (BDL)/IAA12. Together these results provide evidence for the biological relevance of ARF-ARF and ARF-Aux/IAA interaction in Arabidopsis plants and demonstrate that an individual ARF can act in both invariantly programmed pattern formation as well as in conditional responses to external signals.

Arabidopsis↗
PubMed2004

Increased neuromuscular activity causes axonal defects and muscular degeneration.

Before establishing terminal synapses with their final muscle targets, migrating motor axons form en passant synaptic contacts with myotomal muscle. Whereas signaling through terminal synapses has been shown to play important roles in pre- and postsynaptic development, little is known about the function of these early en passant synaptic contacts. Here, we show that increased neuromuscular activity through en passant synaptic contacts affects pre- and postsynaptic development. We demonstrate that in zebrafish twister mutants, prolonged neuromuscular transmission causes motor axonal extension and muscular degeneration in a dose-dependent manner. Cloning of twister reveals a novel, dominant gain-of-function mutation in the muscle-specific nicotinic acetylcholine receptor alpha-subunit, CHRNA1. Moreover, electrophysiological analysis demonstrates that the mutant subunit increases synaptic decay times, thereby prolonging postsynaptic activity. We show that as the first en passant synaptic contacts form, excessive postsynaptic activity in homozygous embryos severely impedes pre- and postsynaptic development, leading to degenerative defects characteristic of the human slow-channel congenital myasthenic syndrome. By contrast, in heterozygous embryos, transient and mild increase in postsynaptic activity does not overtly affect postsynaptic morphology but causes transient axonal defects, suggesting bi-directional communication between motor axons and myotomal muscle. Together, our results provide compelling evidence that during pathfinding, myotomal muscle cells communicate extensively with extending motor axons through en passant synaptic contacts.

Animals↗
PubMed1998

Glial differentiation does not require a neural ground state.

Glial cells differentiate from the neuroepithelium. In flies, gliogenesis depends on the expression of glial cell deficient/glial cell missing (glide/gcm). The phenotype of glide/gcm loss- and gain-of-function mutations suggested that gliogenesis occurs in cells that, by default, would differentiate into neurons. Here we show that glide/gcm is able to induce cells even from a distinct germ layer, the mesoderm, to activate the glial developmental program, which demonstrates that gliogenesis does not require a ground neural state. These findings challenge the common view on the establishment of cell diversity in the nervous system. Strikingly, ectopic glide/gcm overrides positional information by repressing the endogenous developmental program. These findings also indicate that glial differentiation tightly depends on glide/gcm transcriptional regulation. It is likely that glide/gcm homologs act similarly during vertebrate gliogenesis.

Animals↗