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P W Sternberg

Publications and source records attributed to P W Sternberg.

At least 19 recordsLinked to original sources
PubMed1996

Coordinated morphogenesis of epithelia during development of the Caenorhabditis elegans uterine-vulval connection.

Development of the nematode egg-laying system requires the formation of a connection between the uterine lumen and the developing vulval lumen, thus allowing a passage for eggs and sperm. This relatively simple process serves as a model for certain aspects of organogenesis. Such a connection demands that cells in both tissues become specialized to participate in the connection, and that the specialized cells are brought in register. A single cell, the anchor cell, acts to induce and to organize specialization of the epidermal and uterine epithelia, and registrates these tissues. The inductions act via evolutionarily conserved intercellular signaling pathways. The anchor cell induces the vulva from ventral epithelial cells via the LIN-3 growth factor and LET-23 transmembrane tyrosine kinase. It then induces surrounding uterine intermediate precursors via the receptor LIN-12, a founding member of the Notch family of receptors. Both signaling pathways are used multiple times during development of Caenorhabditis elegans. The outcome of the signaling is context-dependent. Both inductions are reciprocated. After the anchor cell has induced the vulva, it stretches toward the induced vulval cells. After the anchor cell has induced specialized uterine intermediate precursor cells, it fuses with a subset of their progeny.

Animals↗
PubMed1996

Evolution of nematode vulval fate patterning.

Nematodes provide a useful experimental system with which to investigate the evolution of development at the cellular, genetic, and molecular levels. Building on an understanding of vulval development in Caenorhabditis elegans, analysis of vulval development has been extended to a number of other species in three families of the Nematode phylum. Changes have occurred in most aspects of vulval development: alteration in the number of cells competent to participate in vulval development by changes in apoptosis; changes in the relative contributions of position-dependent predisposition toward particular fates (prepattern), inductive signaling and lateral signaling; and in the specific lineages generated by vulval precursor cells. Genetic analysis of one species in which only three vulval precursor cells are present identified a mutation that increases the number of vulva precursor cells toward that found in C. elegans.

Animals↗
PubMed1996

Mutations in a C. elegans Gqalpha gene disrupt movement, egg laying, and viability.

We find that C. elegans egl-30 encodes a heterotrimeric G protein a subunit more than 80% identical to mammalian Gqalpha family proteins, and which can function as a Gqalpha subunit in COS-7 cells. We have identified new egl-30 alleles in a selection for genes involved in the C. elegans acetylcholine response. Two egl-30 alleles specify premature termination of Gqalpha and are essentially lethal in homozygotes. Animals homozygous for six other egl-30 alleles are viable and fertile, but exhibit delayed egg laying and leave flattened tracks. Overexpression of the wild-type egl-30 gene produces the opposite behavior. Analysis of these mutants suggest that their phenotypes reflect defects in the muscle or neuromuscular junction.

Amino Acid Sequence↗
PubMed1996

A point mutation in the extracellular domain activates LET-23, the Caenorhabditis elegans epidermal growth factor receptor homolog.

The let-23 gene encodes a Caenorhabditis elegans homolog of the epidermal growth factor receptor (EGFR) necessary for vulval development. We have characterized a mutation of let-23 that activates the receptor and downstream signal transduction, leading to excess vulval differentiation. This mutation alters a conserved cysteine residue in the extracellular domain and is the first such point mutation in the EGFR subfamily of tyrosine kinases. Mutation of a different cysteine in the same subdomain causes a strong loss-of-function phenotype, suggesting that cysteines in this region are important for function and nonequivalent. Vulval precursor cells can generate either of two subsets of vulval cells (distinct fates) in response to sa62 activity. The fates produced depended on the copy number of the mutation, suggesting that quantitative differences in receptor activity influence the decision between these two fates.

Amino Acid Sequence↗
PubMed1996

Symmetry breakage in the development of one-armed gonads in nematodes.

Whereas the hermaphrodite gonad of Caenorhabditis elegans has two symmetric arms (didelphy), the female/hermaphrodite gonad of many nematode species features a single anterior arm (monodelphy). We examined how gonadal cell lineages and intercellular signalling evolve to generate these diverse structures. In C. elegans, the two arms develop symmetrically from two somatic precursor cells, Z1 (anterior) and Z4 (posterior). Each first gives rise to one distal tip cell (which promotes arm growth and germ line proliferation), two ovary precursors and three uterine precursors in the center of the developing gonad. In monodelphic species, Z1 and Z4 have different fates. The first visible asymmetry between them is in the relative timing of their divisions, followed by asymmetric cell movements. The putative posterior distal tip cell is then eliminated in all but one species by programmed cell death. In some species the posterior ovary precursors form a small vestigial posterior arm, the post-vulval sac; in other species, they stay undivided, or die. In Cephalobus sp. PS1197, the specific fate of Z4 progeny is induced by Z1 (or its daughters). In the uterus in C. elegans, symmetric lateral signalling between Z1.ppp and Z4.aaa renders them equally likely to become the anchor cell, which links the uterus to the vulva. In the different monodelphic species, anchor cell specification is biased, or fully fixed, to a descendant of either Z1 or Z4. Replacement regulation upon anchor cell ablation is conserved in some species, but lost in others, leading to a mosaic-type development. Differentiation between Z1 and Z4 is thus manifested at this later stage in the breakage of symmetry of cell interactions in the ventral uterus.

Animals↗
PubMed1995

Similarity of sli-1, a regulator of vulval development in C. elegans, to the mammalian proto-oncogene c-cbl.

Vulval induction during Caenorhabditis elegans development is mediated by LET-23, a homolog of the mammalian epidermal growth factor receptor tyrosine kinase. The sli-1 gene is a negative regulator of LET-23 and is shown here to encode a protein similar to c-Cbl, a mammalian proto-oncoprotein. SLI-1 and c-Cbl share approximately 55 percent amino acid identity over a stretch of 390 residues, which includes a C3HC4 zinc-binding motif known as the RING finger, and multiple consensus binding sites for Src homology 3 (SH3) domains. SLI-1 and c-Cbl may define a new class of proteins that modify receptor tyrosine kinase-mediated signal transduction.

Amino Acid Sequence↗
PubMed1995

Genetic networks.

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Biological Evolution↗
PubMed1995

Different levels of the C. elegans growth factor LIN-3 promote distinct vulval precursor fates.

An invariant spatial pattern of three cell fates (3 degrees-3 degrees-2 degrees-1 degree-2 degrees-3 degrees) is generated from a field of multipotent precursor cells during C. elegans vulval development. We demonstrate that the epidermal growth factor-like domain of the LIN-3 protein can induce either of two distinct vulval cell fates: a high dose of LIN-3 induces a 1 degree fate; a lower dose of LIN-3 induces a 2 degrees fate. A high dose of LIN-3 can also induce adjacent vulval precursor cells to assume 1 degree fates; thus, high levels of LIN-3 can override the lateral signaling that normally inhibits formation of adjacent 1 degree fates. We propose that the invariant pattern of vulval cell fates is generated by a graded distribution of LIN-3 that promotes different vulval fates according to local concentration and by a lateral signal that reinforces this initial bias.

Animals↗
PubMed1995

Participation of the protein Go in multiple aspects of behavior in C. elegans.

The goa-1 gene encoding the alpha subunit of the heterotrimeric guanosine triphosphate-binding protein (G protein) Go from Caenorhabditis elegans is expressed in most neurons, and in the muscles involved in egg laying and male mating. Reduction-of-function mutations in goa-1 caused a variety of behavioral defects including hyperactive movement, premature egg laying, and male impotence. Expression of the activated Go alpha subunit (G alpha o) in transgenic nematodes resulted in lethargic movement, delayed egg laying, and reduced mating efficiency. Induced expression of activated G alpha o in adults was sufficient to cause these phenotypes, indicating that G alpha o mediates behavior through its role in neuronal function and the functioning of specialized muscles.

Amino Acid Sequence↗
PubMed1995

LET-23-mediated signal transduction during Caenorhabditis elegans development.

We are using Caenorhabditis elegans vulval induction to study intercellular signaling and its regulation. Genes required for vulval induction include the LIN-3 transforming alpha-like growth factor, the LET-23 epidermal growth factor (EGF)-receptor-like transmembrane tyrosine kinase, the SEM-5 adaptor protein, LET-60 Ras, and the LIN-45 Raf serine/threonine kinase. Inactivation of this pathway results in a failure of vulval differentiation, the "vulvaless" phenotype. Activation of this pathway either by overexpression of LIN-3, a point mutation in the LET-23 extracellular domain, or hyperactivity of LET-60 Ras results in excessive vulval differentiation, the "multivulva" phenotype. In addition to searching for new genes that act positively in this signaling pathway, we have also characterized genes that negatively regulate this inductive signaling pathway. We find that such negative regulators are functionally redundant: mutation of only one of these negative regulators has no effect on vulval differentiation; however, if particular combinations of these genes are inactivated, excessive vulval differentiation occurs. The LIN-15 locus encodes two functionally redundant products, LIN-15A and LIN-15B, that formally act upstream of the LET-23 receptor to prevent its activity in the absence of inductive signal. The LIN-15A and B proteins are novel and unrelated to each other. The unc-101, sli-1, and rok-1 genes encode a distinct set of negative regulators of vulval differentiation. The unc-101 gene encodes an adaptin, proposed to be involved in intracellular protein trafficking. The sli-1 gene encodes a protein with similarity to c-cbl, a mammalian proto-oncogene not previously linked with a tyrosine kinase-Ras-mediated signaling pathway. LIN-3 and LET-23 are required for several aspects of C. elegans development--larval viability, P12 neuroectoblast specification, hermaphrodite vulval induction and fertility, and three inductions during male copulatory spicule development. Fertility and vulval differentiation appear to be mediated by distinct parts of the cytoplasmic tail of LET-23, and by distinct signal transduction pathways.

Animals↗
PubMed1995

Evolution of cell lineage and pattern formation in the vulval equivalence group of rhabditid nematodes.

During the formation of the vulva in many nematode hermaphrodites or females, pattern formation, induction, and cell specification can readily be studied at a single-cell level. Nematodes thus allow an evolutionary analysis of developmental processes. We have analyzed cell lineages and pattern formation in the vulva equivalence group of six rhabditid nematodes of the genera Oscheius, Rhabditella, Rhabditoides, Pelodera, and Protorhabditis. The comparison of these species with four previously analyzed species of this family reveals evolutionary modification at several levels. The number of vulva precursor cells (VPCs) differ among species. Of the three particular cell lineages (1 degree, 2 degrees, and 3 degrees) generated by the vulva precursor cells in Caenorhabditis, two (2 degrees and 3 degrees) are altered, whereas the third lineage (1 degree) is conserved among the analyzed species. While most vulval lineages are invariant, we observe variability of the 3 degrees lineage in Pelodera with respect to the number of precursor cells adopting this fate and the number of progeny formed. In two species, the 3 degrees lineage generates an asymmetrical set of cells, oriented by the gonad. In Protorhabditis we frequently find animals with an additional or altered set of VPCs forming vulval tissue.

Animals↗
PubMed1995

Mutations in the Caenorhabditis elegans gene vab-3 reveal distinct roles in fate specification and unequal cytokinesis in an asymmetric cell division.

Asymmetric cell divisions in which a precursor cell distributes fate potential unequally between the two daughter cells represent one of the major mechanisms for fate specification during development. Such mechanisms suggest at least two distinct cellular activities: factors that act to establish asymmetry in the precursor cell and factors that are distributed or activated unequally and function to make the daughter cells different from each other. In Caenorhabditis elegans, cytokinesis of the first division of the male-specific postembryonic blast cell B is unequal, and the two daughters adopt different fates. Others have observed that the genes lin-17 and lin-44 are required, respectively, to establish and to orient this asymmetric division. Mutations in lin-17 and lin-44 coordinately disrupt cytokinesis and fate specification. We describe the function of the gene vab-3 in the B cell lineage. Mutations in vab-3 disrupt the fate of the anterior daughter of B, B.a. However, unlike lin-17 and lin-44, mutations in vab-3 can disrupt fate without the corresponding disruption of unequal cytokinesis. Analysis of lin-17;vab-3 double mutants suggests that vab-3 acts after lin-17 for B.a. fate specification. Double mutant analysis has also identified additional functions of lin-17 in the B lineage subsequent to this first division.

Animals↗
PubMed1995

Sensory regulation of male mating behavior in Caenorhabditis elegans.

C. elegans male mating behavior comprises a series of steps: response to contact with the hermaphrodite, backing along her body, turning around her head or tail, location of the vulva, insertion of the two copulatory spicules into the vulva, and sperm transfer. By ablation of male-specific copulatory structures and their associated neurons, we have identified sensory structures and neurons that participate in each of these steps: the sensory rays mediate response to contact and turning; the hook, the postcloacal sensilla, and the spicules mediate vulva location; the spicules also mediate spicule insertion and regulate sperm transfer. Generally, successful completion of each step places the male in a position to receive a cue for the next step in the pathway. However, the high degree of sensory regulation allows the male to execute some steps independently.

Animals↗
PubMed1995

Ras pathways in Caenorhabditis elegans.

The let-60 ras gene of Caenorhabditis elegans is required for multiple aspects of development. The vulvar differentiation pathway is the most intensively studied of these, but the ras pathway has now been shown to also be essential for male spicule development. Using vulval differentiation, molecular genetic techniques are now being used to study structure/function relationships of particular signaling components and to identify new positively and negatively acting proteins of Ras-mediated signaling pathways. Mutations affecting LET-23, a receptor tyrosine kinase homolog, which cause tissue-specific defects have been localized to the carboxyl terminus. SH2 domain specificity has been analyzed through Src/SEM-5 chimeric proteins in transgenic nematodes. A mitogen-activated protein kinase that acts downstream of LET-60 Ras in vulval differentiation has been identified. Negative regulatory genes have been cloned and found to encode novel proteins and a clathrin adaptor protein.

Amino Acid Sequence↗
PubMed1995

sli-1, a negative regulator of let-23-mediated signaling in C. elegans.

By screening for suppressors of hypomorphic mutations of let-23, a receptor tyrosine kinase necessary for vulval induction in Caenorhabditis elegans, we recovered > or = 12 mutations defining the sli-1 (suppressor of lineage defect) locus. sli-1 mutations suppress four of five phenotypes associated with hypomorphic alleles of let-23 but do not suppress let-23 null alleles. Thus, a sli-1 mutation does not bypass the requirement for functional let-23 but rather allows more potent LET-23-dependent signaling. Mutations at the sli-1 locus are otherwise silent with respect to vulval differentiation and cause only a low-penetrance abnormal head phenotype. Mutations at sli-1 also suppress the vulval defects but not other defects associated with mutations of sem-5, whose product likely interacts with LET-23 protein during vulval induction. Mutations at sli-1 suppress lin-2, lin-7 and lin-10 mutations but only partially suppress lin-3 and let-60 mutations and do not suppress a lin-45 mutation. The sli-1 locus displays dosage sensitivity: severe reduction of function alleles of sli-1 are semidominant suppressors; a duplication of the sli-1(+) region enhances the vulvaless phenotype of hypomorphic mutations of let-23. We propose that sli-1 is a negative regulator that acts at or near the LET-23-mediated step of the vulval induction pathway. Our analysis suggests that let-23 can activate distinct signaling pathways in different tissues: one pathway is required for vulval induction; another pathway is involved in hermaphrodite fertility and is not regulated by sli-1.

Alleles↗
PubMed1995

The Caenorhabditis elegans lin-12 gene mediates induction of ventral uterine specialization by the anchor cell.

The anchor cell (AC) of the Caenorhabditis elegans gonad has a critical role in the development of a functional egg-laying system, which is accomplished through cell-cell interactions. Lateral inhibitory lin-12-mediated signaling among two bipotential cells causes one to adopt the ventral uterine precursor (VU) cell fate while the other becomes the AC. The AC then induces formation of vulval tissue. We find that the AC also induces a particular ventral uterine intermediate precursor fate (pi) by a mechanism that is genetically and temporally distinct from vulval induction. This process requires lin-12, but unlike previously described lin-12-mediated decisions, signaling is unidirectional, is between dissimilar cells and does not involve lateral inhibition. The pi fates are necessary for egg laying and appear to produce a distinct specialized cell type. Thus, patterning of the ventral uterus by the AC is crucial to the development of a functional egg-laying system.

Animals↗
PubMed1994

The identification of a Caenorhabditis elegans homolog of p34cdc2 kinase.

We have identified a Caenorhabditis elegans homolog of p34cdc2 kinase. The C. elegans homolog, ncc-1, is approximately 60% identical to p34cdc2 of Homo sapiens. When expressed from a constitutive yeast promoter, ncc-1 is capable of complementing a conditional lethal mutation in the CDC28 gene of Saccharomyces cerevisiae, indicating that this C. elegans homolog can properly regulate the cell cycle.

Amino Acid Sequence↗