The role of the NK-homeobox gene slouch (S59) in somatic muscle patterning

Development ◽  
1999 ◽  
Vol 126 (20) ◽  
pp. 4525-4535 ◽  
Author(s):  
S. Knirr ◽  
N. Azpiazu ◽  
M. Frasch
Keyword(s):  
Muscle Development ◽  
Ectopic Expression ◽  
Homeobox Gene ◽  
Drosophila Embryo ◽  
Loss Of Function ◽  
Cell Fates ◽  
Somatic Muscle ◽  
Gene Encoding ◽  
Body Wall Muscles ◽  
Founder Cells

In the Drosophila embryo, a distinct class of myoblasts, designated as muscle founders, prefigures the mature pattern of somatic body wall muscles. Each founder cell appears to be instrumental in generating a single larval muscle with a defined identity. The NK homeobox gene S59 was the first of a growing number of proposed ‘identity genes’ that have been found to be expressed in stereotyped patterns in specific subsets of muscle founders and their progenitor cells and are thought to control their developmental fates. In the present study, we describe the effects of gain- and loss-of-function experiments with S59. We find that a null mutation in the gene encoding S59, which we have named slouch (slou), disrupts the development of all muscles that are derived from S59-expressing founder cells. The observed phenotypes upon mutation and ectopic expression of slouch include transformations of founder cell fates, thus confirming that slouch (S59) functions as an identity gene in muscle development. These fate transformations occur between sibling founder cells as well as between neighboring founders that are not lineage-related. In the latter case, we show that slouch (S59) activity is required cell-autonomously to repress the expression of ladybird (lb) homeobox genes, thereby preventing specification along the lb pathway. Together, these findings provide new insights into the regulatory interactions that establish the somatic muscle pattern.

An activity gradient of decapentaplegic is necessary for the specification of dorsal pattern elements in the Drosophila embryo

Development ◽  
1993 ◽  
Vol 117 (2) ◽  
pp. 807-822 ◽  
Author(s):  
K.A. Wharton ◽  
R.P. Ray ◽  
W.M. Gelbart
Keyword(s):  
Cell Fate ◽  
Gene Dosage ◽  
Early Embryo ◽  
Drosophila Embryo ◽  
Cell Fates ◽  
Gene Encoding ◽  
In The Wild ◽  
Intercellular Signalling ◽  
Overlapping Domains ◽  
Dorsal Pattern

decapentaplegic (dpp) is a zygotically expressed gene encoding a TGF-beta-related ligand that is necessary for dorsal-ventral patterning in the Drosophila embryo. We show here that dpp is an integral part of a gradient that specifies many different cell fates via intercellular signalling. There is a graded requirement for dpp activity in the early embryo: high levels of dpp activity specify the amnioserosa, while progressively lower levels specify dorsal and lateral ectoderm. This potential for dpp to specify cell fate is highly dosage sensitive. In the wild-type embryo, increasing the gene dosage of dpp can shift cell fates along the dorsal-ventral axis. Furthermore, in mutant embryos, in which only a subset of the dorsal-ventral pattern elements are represented, increasing the gene dosage of dpp can specifically transform those pattern elements into more dorsal ones. We present evidence that the zygotic dpp gradient and the maternal dorsal gradient specify distinct, non-overlapping domains of the dorsal-ventral pattern.

Regulation of dorsal-ventral patterning: the ventralizing effects of the novel Xenopus homeobox gene Vox

Development ◽  
1996 ◽  
Vol 122 (6) ◽  
pp. 1711-1721 ◽  
Author(s):  
J.E. Schmidt ◽  
G. von Dassow ◽  
D. Kimelman
Keyword(s):  
Dynamic Process ◽  
Regulatory Network ◽  
Ectopic Expression ◽  
Homeobox Gene ◽  
Normal Function ◽  
Dorsal Side ◽  
Neural Plate ◽  
The Novel ◽  
Cell Fates ◽  
Early Developmental

The formation of the dorsal-ventral axis in Xenopus laevis is elicited by a signaling cascade on the dorsal side of the embryo initiated by cortical rotation. These early developmental events impart an initial axial polarity to the embryo. By the time gastrulation occurs, the embryo has established opposing dorsal and ventral regulatory regions. Through a dynamic process, the embryo acquires a definitive pattern that reflects the distribution of future cell fates. Here we present a novel homeobox gene, Vox, whose expression reflects this dynamic process. Vox is first expressed throughout the embryo and subsequently eliminated from the notochord and neural plate. Ectopic expression of Vox demonstrates that the normal function of this gene may be to suppress dorsal genes such as Xnot and chordin, and induce ventral and paraxial genes such as Bmp-4 and MyoD. Ectopic expression of BMP-4 ventralizes embryos and positively regulates the expression of Vox, suggesting that these genes are components of a reciprocal regulatory network.

The role of the msh homeobox gene during Drosophila neurogenesis: implication for the dorsoventral specification of the neuroectoderm

Development ◽  
1997 ◽  
Vol 124 (16) ◽  
pp. 3099-3109 ◽  
Author(s):  
T. Isshiki ◽  
M. Takeichi ◽  
A. Nose
Keyword(s):  
Cell Fate ◽  
Neural Development ◽  
Ectopic Expression ◽  
Homeobox Gene ◽  
Loss Of Function ◽  
Spinal Cord Development ◽  
Dorsal Portion ◽  
Msx Genes

Development of the Drosophila central nervous system begins with the delamination of neural and glial precursors, called neuroblasts, from the neuroectoderm. An early and important step in the generation of neural diversity is the specification of individual neuroblasts according to their position. In this study, we describe the genetic analysis of the msh gene which is likely to play a role in this process. The msh/Msx genes are one of the most highly conserved families of homeobox genes. During vertebrate spinal cord development, Msx genes (Msx1-3) are regionally expressed in the dorsal portion of the developing neuroectoderm. Similarly in Drosophila, msh is expressed in two longitudinal bands that correspond to the dorsal half of the neuroectoderm, and subsequently in many dorsal neuroblasts and their progeny. We showed that Drosophila msh loss-of-function mutations led to cell fate alterations of neuroblasts formed in the dorsal aspect of the neuroectoderm, including a possible dorsal-to-ventral fate switch. Conversely, ectopic expression of msh in the entire neuroectoderm severely disrupted the proper development of the midline and ventral neuroblasts. The results provide the first in vivo evidence for the role of the msh/Msx genes in neural development, and support the notion that they may perform phylogenetically conserved functions in the dorsoventral patterning of the neuroectoderm.

The Homeobox Gene cut Interacts Genetically With the Homeotic Genes proboscipedia and Antennapedia

Genetics ◽  
1998 ◽  
Vol 149 (1) ◽  
pp. 131-142
Author(s):  
Laura A Johnston ◽  
Bruce D Ostrow ◽  
Christine Jasoni ◽  
Karen Blochlinger
Keyword(s):  
Expression Patterns ◽  
Significant Proportion ◽  
Ectopic Expression ◽  
Homeobox Gene ◽  
Homeodomain Protein ◽  
Homeotic Genes ◽  
Loss Of Function ◽  
Regulation Of Expression ◽  
Segmental Identity

Abstract The cut locus (ct) codes for a homeodomain protein (Cut) and controls the identity of a subset of cells in the peripheral nervous system in Drosophila. During a screen to identify ct-interacting genes, we observed that flies containing a hypomorphic ct mutation and a heterozygous deletion of the Antennapedia complex exhibit a transformation of mouthparts into leg and antennal structures similar to that seen in homozygous proboscipedia (pb) mutants. The same phenotype is produced with all heterozygous pb alleles tested and is fully penetrant in two different ct mutant backgrounds. We show that this phenotype is accompanied by pronounced changes in the expression patterns of both ct and pb in labial discs. Furthermore, a significant proportion of ct mutant flies that are heterozygous for certain Antennapedia (Antp) alleles have thoracic defects that mimic loss-of-function Antp phenotypes, and ectopic expression of Cut in antennal discs results in ectopic Antp expression and a dominant Antp-like phenotype. Our results implicate ct in the regulation of expression and/or function of two homeotic genes and document a new role of ct in the control of segmental identity.

scholarly journals Dimerization partners determine the activity of the Twist bHLH protein during Drosophila mesoderm development

Development ◽  
2001 ◽  
Vol 128 (16) ◽  
pp. 3145-3159 ◽  
Author(s):  
Irinka Castanon ◽  
Stephen Von Stetina ◽  
Jason Kass ◽  
Mary K. Baylies
Keyword(s):  
Cell Fate ◽  
Muscle Development ◽  
Bhlh Protein ◽  
Mesoderm Induction ◽  
Loss Of Function ◽  
Somatic Muscle ◽  
Cell Fate Decisions ◽  
Sequence Of Events

The basic helix-loop-helix transcription factor Twist regulates a series of distinct cell fate decisions within the Drosophila mesodermal lineage. These twist functions are reflected in its dynamic pattern of expression, which is characterized by initial uniform expression during mesoderm induction, followed by modulated expression at high and low levels in each mesodermal segment, and finally restricted expression in adult muscle progenitors. We show two distinct partner-dependent functions for Twist that are crucial for cell fate choice. We find that Twist can form homodimers and heterodimers with the Drosophila E protein homologue, Daughterless,in vitro. Using tethered dimers to assess directly the function of these two particular dimers in vivo, we show that Twist homodimers specify mesoderm and the subsequent allocation of mesodermal cells to the somatic muscle fate. Misexpression of Twist-tethered homodimers in the ectoderm or mesoderm leads to ectopic somatic muscle formation overriding other developmental cell fates. In addition, expression of tethered Twist homodimers in embryos null fortwist can rescue mesoderm induction as well as somatic muscle development. Loss of function analyses, misexpression and dosage experiments, and biochemical studies indicate that heterodimers of Twist and Daughterless repress genes required for somatic myogenesis. We propose that these two opposing roles explain how modulated Twist levels promote the allocation of cells to the somatic muscle fate during the subdivision of the mesoderm. Moreover, this work provides a paradigm for understanding how the same protein controls a sequence of events within a single lineage.

Sloppy paired acts as the downstream target of wingless in the Drosophila CNS and interaction between sloppy paired and gooseberry inhibits sloppy paired during neurogenesis

Development ◽  
2000 ◽  
Vol 127 (3) ◽  
pp. 655-665 ◽  
Author(s):  
K.M. Bhat ◽  
E.H. van Beers ◽  
P. Bhat
Keyword(s):  
Target Gene ◽  
Ectopic Expression ◽  
Drosophila Embryo ◽  
Loss Of Function ◽  
Heterologous Promoter ◽  
Neuronal Precursor ◽  
Downstream Target ◽  
Wnt Proteins ◽  
Neuronal Lineage ◽  
Neuronal Precursor Cell

Wingless (Wg) and other Wnt proteins play a crucial role in a number of developmental decisions in a variety of organisms. In the ventral nerve cord of the Drosophila embryo, Wg is non-autonomously required for the formation and specification of a neuronal precursor cell, NB4-2. NB4-2 gives rise to a well-studied neuronal lineage, the RP2/sib lineage. While the various components of the Wg-signaling pathway are also required for generating NB4-2, the target gene(s) of this pathway in the signal-receiving cell is not known. In this paper, we show that sloppy paired 1 and sloppy paired 2 function as the downstream targets of the Wg signaling to generate the NB4-2 cell. Thus, while the loss-of-function mutations in wg and slp have the same NB4-2 formation and specification defects, these defects in wg mutants can be rescued by expressing slp genes from a heterologous promoter. That slp genes function downstream of the Wg signaling is also indicated by the result that expression of slp genes is lost from the neuroectoderm in wg mutants and that ectopic expression of wg induces ectopic expression of slp. Finally, previous results show that Gooseberry (Gsb) prevents Wg from specifying NB4-2 identity to the wg-expressing NB5-3. In this paper, we also show that gsb interacts with slp and prevents Slp from specifying NB4-2 identity. Overexpression of slp overcomes this antagonistic interaction and respecifies NB5-3 as NB4-2. This respecification, however, can be suppressed by a simultaneous overexpression of gsb at high levels. This mechanism appears to be responsible for specifying NB5-3 identity to a row 5 neuroblast and preventing Wg from specifying NB4-2 identity to that cell.

Drosophila-Raf Acts to Elaborate Dorsoventral Pattern in the Ectoderm of Developing Embryos

Genetics ◽  
2001 ◽  
Vol 159 (3) ◽  
pp. 1031-1044
Author(s):  
Kori Radke ◽  
Kimberly Johnson ◽  
Rong Guo ◽  
Anne Davidson ◽  
Linda Ambrosio
Keyword(s):  
Egf Receptor ◽  
Drosophila Embryo ◽  
Functional Requirements ◽  
Loss Of Function ◽  
Maternal Role ◽  
Partial Loss ◽  
Cell Fates ◽  
Regulatory Domains ◽  
Early Drosophila Embryo ◽  
Lateral Cell

Abstract In the early Drosophila embryo the activity of the EGF-receptor (Egfr) is required to instruct cells to adopt a ventral neuroectodermal fate. Using a gain-of-function mutation we showed that D-raf acts to transmit this and other late-acting embryonic Egfr signals. A novel role for D-raf was also identified in lateral cell development using partial loss-of-function D-raf mutations. Thus, we provide evidence that zygotic D-raf acts to specify cell fates in two distinct pathways that generate dorsoventral pattern within the ectoderm. These functional requirements for D-raf activity occur subsequent to its maternal role in organizing the anterioposterior axis. The consequences of eliminating key D-raf regulatory domains and specific serine residues in the transmission of Egfr and lateral epidermal signals were also addressed here.

Muscle pattern diversification in Drosophila is determined by the autonomous function of homeotic genes in the embryonic mesoderm

Development ◽  
1994 ◽  
Vol 120 (4) ◽  
pp. 755-768 ◽  
Author(s):  
A.M. Michelson
Keyword(s):  
Ectopic Expression ◽  
Drosophila Embryo ◽  
Inhibitory Influence ◽  
Homeotic Genes ◽  
Bithorax Complex ◽  
Cell Fates ◽  
Autonomous Action ◽  
Autonomous Function ◽  
Attachment Sites ◽  
Muscle Attachment Sites

Muscle diversification in the Drosophila embryo is manifest in a stereotyped array of myofibers that exhibit distinct segment-specific patterns. Here it is shown that the homeotic genes of the Bithorax complex control the identities of abdominal somatic muscles and their precursors by functioning directly in cells of the mesoderm. Whereas Ultrabithorax (Ubx) and abdominal-A (abd-A) have equivalent functions in promoting the formation of particular muscle precursors in the anterior abdominal segments, Abdominal-B (Abd-B) suppresses the development of these same myogenic cells in the posterior region of the abdomen. When expressed in the same mesodermal cells, however, either UBX or ABD-A can override the inhibitory influence of ABD-B, suggesting that these factors may compete in the regulation of common downstream genes. Furthermore, targeted ectopic expression of Ubx or abd-A indicates that these homeotic genes influence muscle cell fates by autonomous action in mesodermal cells. Muscle identity also appears to be sensitive to the level of UBX in myogenic precursors. Finally, these experiments reveal that homeotic cues specific to both the mesoderm and the ectoderm cooperate to specify the pattern of muscle attachment sites.

scholarly journals Ssdp influences Wg expression and embryonic somatic muscle identity in Drosophila melanogaster

2021 ◽  
Author(s):  
Preethi Poovathumkadavil ◽  
Jean-Philippe Da Ponte ◽  
Krzysztof Jagla
Keyword(s):  
Skeletal Muscles ◽  
Muscle Development ◽  
Loss Of Function ◽  
Core Component ◽  
Somatic Muscle ◽  
Specific Expression ◽  
Vertebrate Muscle ◽  
Evolutionarily Conserved ◽  
Epidermal Expression ◽  
Somatic Muscles

The somatic muscles of the Drosophila embryo and larvae share structural and functional similarities with vertebrate skeletal muscles and serve as a powerful model for studying muscle development. Here we show that the evolutionarily conserved Ssdp protein is required for the correct patterning of somatic muscles. Ssdp is part of the conserved Chi/LDB-Ssdp (ChiLS) complex that is a core component of the conserved Wg/Wnt enhanceosome, which responds to Wg signals to regulate gene transcription. Ssdp shows isoform specific expression in developing somatic muscles and its loss of function leads to an aberrant somatic muscle pattern due to a deregulated muscle identity program. Ssdp mutant embryos fail to maintain adequate expression levels of muscle identity transcription factors and this results in aberrant muscle morphology, innervation, attachment and fusion. We also show that the epidermal expression of Wg is downregulated in Ssdp mutants and that Ssdp interacts with Wg to regulate the properties of a subset of ventral muscles. Thus, our data unveil the dual contribution of Ssdp to muscle diversification by regulating the expression of muscle-intrinsic identity genes and by interacting with the extrinsic factor, Wg. The knowledge gained here about Ssdp and its interaction with Wg could be relevant to vertebrate muscle development.

scholarly journals Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Nathan L Absalom ◽  
Vivian W Y Liao ◽  
Kavitha Kothur ◽  
Dinesh C Indurthi ◽  
Bruce Bennetts ◽  
...  
Keyword(s):  
De Novo ◽  
Drug Effects ◽  
Receptor Expression ◽  
Aminobutyric Acid ◽  
Loss Of Function ◽  
Molecular Phenotype ◽  
Gain Of Function ◽  
Gene Encoding ◽  
Epileptic Encephalopathies ◽  
Receptor Phenotype

Abstract Variants in the GABRB3 gene encoding the β3-subunit of the γ-aminobutyric acid type A ( receptor are associated with various developmental and epileptic encephalopathies. Typically, these variants cause a loss-of-function molecular phenotype whereby γ-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits γ-aminobutyric acid transaminase to increase tonic γ-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different γ-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic γ-aminobutyric acid A receptor construct, to resemble the γ-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of γ-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of γ-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants.

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