The Hox gene lin-39 is required during C. elegans vulval induction to select the outcome of Ras signaling

Development ◽  
1998 ◽  
Vol 125 (2) ◽  
pp. 181-190 ◽  
Author(s):  
J.N. Maloof ◽  
C. Kenyon
Keyword(s):  
Body Region ◽  
Ras Signaling ◽  
Cell Fates ◽  
Vulval Development ◽  
Ras Pathway ◽  
Hox Gene ◽  
C Elegans ◽  
Cell Divisions ◽  
Ras Activation ◽  
Vulval Precursor Cells

The Ras signaling pathway specifies a variety of cell fates in many organisms. However, little is known about the genes that function downstream of the conserved signaling cassette, or what imparts the specificity necessary to cause Ras activation to trigger different responses in different tissues. In C. elegans, activation of the Ras pathway induces cells in the central body region to generate the vulva. Vulval induction takes place in the domain of the Hox gene lin-39. We have found that lin-39 is absolutely required for Ras signaling to induce vulval development. During vulval induction, the Ras pathway, together with basal lin-39 activity, up-regulates lin-39 expression in vulval precursor cells. We find that if lin-39 function is absent at this time, no vulval cell divisions occur. Furthermore, if lin-39 is replaced with the posterior Hox gene mab-5, then posterior structures are induced instead of a vulva. Our findings suggest that in addition to permitting vulval cell divisions to occur, lin-39 is also required to specify the outcome of Ras signaling by selectively activating vulva-specific genes.

The Pristionchus HOX gene Ppa-lin-39 inhibits programmed cell death to specify the vulva equivalence group and is not required during vulval induction

Development ◽  
1998 ◽  
Vol 125 (19) ◽  
pp. 3865-3873 ◽  
Author(s):  
R.J. Sommer ◽  
A. Eizinger ◽  
K.Z. Lee ◽  
B. Jungblut ◽  
A. Bubeck ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Nematode Species ◽  
Precursor Cells ◽  
Body Region ◽  
Ras Signaling ◽  
Equivalence Group ◽  
Hox Gene ◽  
C Elegans ◽  
Vulval Precursor Cells

In the two nematode species Caenorhabditis elegans and Pristionchus pacificus the vulva equivalence group in the central body region is specified by the Hox gene lin-39. C. elegans lin-39 mutants are vulvaless and the vulval precursor cells fuse with the surrounding hypodermis, whereas in P. pacificus lin-39 mutants the vulval precursor cells die by apoptosis. Mechanistically, LIN-39 might inhibit non-vulval fate (cell fusion in C. elegans, apoptosis in P. pacificus), promote vulval fate or do both. To study the mechanism of lin-39 function, we isolated P. pacificus cell death mutants and identified mutations in ced-3. Surprisingly, P. pacificus ced-3; lin-39 double mutants form a functional vulva in the absence of LIN-39 activity. Thus, in P. pacificus lin-39 specifies the vulva equivalence group by inhibiting programmed cell death. Furthermore, these data reveal an important difference in a later function of lin-39 between the two species. In C. elegans, LIN-39 specifies vulval cell fates in response to inductive RAS signaling, and in P. pacificus LIN-39 is not required for vulval induction. Thus, the comparative analysis indicates that lin-39 has distinct functions in both species although the gene is acting in a homologous developmental system.

The beta-catenin homolog BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development

Development ◽  
1998 ◽  
Vol 125 (18) ◽  
pp. 3667-3680 ◽  
Author(s):  
D.M. Eisenmann ◽  
J.N. Maloof ◽  
J.S. Simske ◽  
C. Kenyon ◽  
S.K. Kim
Keyword(s):  
Signaling Pathway ◽  
Cell Fate ◽  
Precursor Cell ◽  
Ras Signaling ◽  
Beta Catenin ◽  
Cell Fates ◽  
Vulval Development ◽  
Hox Gene ◽  
C Elegans ◽  
Vulval Precursor Cell

In C. elegans, the epithelial Pn.p cells adopt either a vulval precursor cell fate or fuse with the surrounding hypodermis (the F fate). Our results suggest that a Wnt signal transduced through a pathway involving the beta-catenin homolog BAR-1 controls whether P3.p through P8.p adopt the vulval precursor cell fate. In bar-1 mutants, P3.p through P8.p can adopt F fates instead of vulval precursor cell fates. The Wnt/bar-1 signaling pathway acts by regulating the expression of the Hox gene lin-39, since bar-1 is required for LIN-39 expression and forced lin-39 expression rescues the bar-1 mutant phenotype. LIN-39 activity is also regulated by the anchor cell signal/let-23 receptor tyrosine kinase/let-60 Ras signaling pathway. Our genetic and molecular experiments show that the vulval precursor cells can integrate the input from the BAR-1 and LET-60 Ras signaling pathways by coordinately regulating activity of the common target LIN-39 Hox.

Cell fates and fusion in theC. elegansvulval primordium are regulated by the EGL-18 and ELT-6 GATA factors — apparent direct targets of the LIN-39 Hox protein

Development ◽  
2002 ◽  
Vol 129 (22) ◽  
pp. 5171-5180 ◽  
Author(s):  
Kyunghee Koh ◽  
Sara M. Peyrot ◽  
Cricket G. Wood ◽  
Javier A. Wagmaister ◽  
Morris F. Maduro ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Body Region ◽  
Embryonic Cells ◽  
Cell Fates ◽  
Hox Gene ◽  
C Elegans ◽  
Gata Factors ◽  
Vulval Precursor Cells ◽  
Hox Protein ◽  
Larval Lethality

Development of the vulva in C. elegans is mediated by the combinatorial action of several convergent regulatory inputs, three of which,the Ras, Wnt and Rb-related pathways, act by regulating expression of thelin-39 Hox gene. LIN-39 specifies cell fates and regulates cell fusion in the mid-body region, leading to formation of the vulva. In the lateral seam epidermis, differentiation and cell fusion have been shown to be regulated by two GATA-type transcription factors, ELT-5 and -6. We report that ELT-5 is encoded by the egl-18 gene, which was previously shown to promote formation of a functional vulva. Furthermore, we find that EGL-18(ELT-5), and its paralogue ELT-6, are redundantly required to regulate cell fates and fusion in the vulval primordium and are essential to form a vulva. Elimination of egl-18 and elt-6 activity results in arrest by the first larval stage; however, in animals rescued for this larval lethality by expression of ELT-6 in non-vulval cells, the post-embryonic cells(P3.p-P8.p) that normally become vulval precursor cells often fuse with the surrounding epidermal syncytium or undergo fewer than normal cell divisions,reminiscent of lin-39 mutants. Moreover, egl-18/elt-6reporter gene expression in the developing vulva is attenuated inlin-39(rf) mutants, and overexpression of egl-18 can partially rescue the vulval defects caused by reduced lin-39activity. LIN-39/CEH-20 heterodimers bind two consensus HOX/PBC sites in a vulval enhancer region of egl-18/elt-6, one of which is essential for vulval expression of egl-18/elt-6 reporter constructs. These findings demonstrate that the EGL-18 and ELT-6 GATA factors are essential, genetically redundant regulators of cell fates and fusion in the developing vulva and are apparent direct transcriptional targets of the LIN-39 Hox protein.

scholarly journals Cell fate patterning during C. elegans vulval development

Development ◽  
1993 ◽  
Vol 119 (Supplement) ◽  
pp. 9-18 ◽  
Author(s):  
Russell J. Hill ◽  
Paul W. Sternberg
Keyword(s):  
Cell Fate ◽  
Short Range ◽  
Precursor Cells ◽  
Cell Fates ◽  
Vulval Development ◽  
C Elegans ◽  
Vulval Precursor Cells ◽  
Combined Action ◽  
Anchor Cell ◽  
Inductive Signal

Precursor cells of the vulva of the C. elegans hermaphrodite choose between two vulval cell fates (1° and 2°) and a non-vulval epidermal fate (3°) in response to three intercellular signals. An inductive signal produced by the anchor cell induces the vulval precursors to assume the 1° and 2° vulval fates. This inductive signal is an EGF-like growth factor encoded by the gene lin-3. An inhibitory signal mediated by lin-15, and which may originate from the surrounding epidermis, prevents the vulval precursors from assuming vulval fates in the absence of the inductive signal. A short range lateral signal, which acts through the gene lin-12, regulates the pattern of 1° and 2° fates assumed by the induced vulval precursors. The combined action of the three signals precisely directs the six vulval precursors to adopt a 3° 3° 2° 1° 2 ° 3° pattern of fates. The amount of inductive signal produced by the anchor cell appears to determine the number or vulval precursors that assume vulval fates. The three induced vulval precursors most proximal to the anchor cell are proposed to adopt the 2° 1° 2° pattern of fates in response to a gradient of the inductive signal and also in response to lateral signalling that inhibits adjacent vulval precursor cells from both assuming the 1° fate.

scholarly journals Insulated Switches: Dual-Function Protein RalGEFRGL-1 Promotes Developmental Fidelity

2020 ◽  
Vol 21 (20) ◽  
pp. 7610 ◽  
Author(s):  
Tam Duong ◽  
Neal R. Rasmussen ◽  
David J. Reiner
Keyword(s):  
Birth Defects ◽  
Dual Function ◽  
Wild Type ◽  
Cell Fates ◽  
Vulval Development ◽  
C Elegans ◽  
Vulval Precursor Cells ◽  
Anchor Cell ◽  
The Impact ◽  
Wild Type Control

The C. elegans vulva is an excellent model for the study of developmental biology and cell–cell signaling. The developmental induction of vulval precursor cells (VPCs) to assume the 3°-3°-2°-1°-2°-3° patterning of cell fates occurs with 99.8% accuracy. During C. elegans vulval development, an EGF signal from the anchor cell initiates the activation of RasLET-60 > RafLIN-45 > MEKMEK-2 > ERKMPK-1 signaling cascade to induce the 1° cell. The presumptive 1° cell signals its two neighboring cells via NotchLIN-12 to develop 2° cells. In addition, RasLET-60 switches effectors to RalGEFRGL-1 > RalRAL-1 to promote 2° fate. Shin et al. (2019) showed that RalGEFRGL-1 is a dual-function protein in VPCs fate patterning. RalGEFRGL-1 functions as a scaffold for PDKPDK-1 > AktAKT-1/2 modulatory signaling to promote 1° fate in addition to propagating the RasLET-60 modulatory signal through RalRAL-1 to promote 2° fate. The deletion of RalGEFRGL-1 increases the frequency of VPC patterning errors 15-fold compared to the wild-type control. We speculate that RalGEFRGL-1 represents an “insulated switch”, whereby the promotion of one signaling activity curtails the promotion of the opposing activity. This property might increase the impact of the switch on fidelity more than two separately encoded proteins could. Understanding how developmental fidelity is controlled will help us to better understand the origins of cancer and birth defects, which occur in part due to the misspecification of cell fates.

scholarly journals Mutations in cye-1, a Caenorhabditis elegans cyclin E homolog, reveal coordination between cell-cycle control and vulval development

Development ◽  
2000 ◽  
Vol 127 (18) ◽  
pp. 4049-4060 ◽  
Author(s):  
D.S. Fay ◽  
M. Han
Keyword(s):  
Cell Cycle ◽  
Cyclin E ◽  
Cell Cycle Control ◽  
Terminal Differentiation ◽  
Loss Of Function ◽  
Cell Fates ◽  
Vulval Development ◽  
C Elegans ◽  
Vulval Precursor Cells ◽  
Specific Number

We have identified strong loss-of-function mutations in the C. elegans cyclin E gene, cye-1. Mutations in cye-1 lead to the underproliferation of many postembryonic blast lineages as well as defects in fertility and gut-cell endoreduplication. In addition, cye-1 is required maternally, but not zygotically for embryonic development. Our analysis of vulval development in cye-1 mutants suggests that a timing mechanism may control the onset of vulval cell terminal differentiation: once induced, these cells appear to differentiate after a set amount of time, rather than a specific number of division cycles. cye-1 mutants also show an increase in the percentage of vulval precursor cells (VPCs) that adopt vulval cell fates, indicating that cell-cycle length can play a role in the proper patterning of vulval cells. By analyzing cul-1 mutants, we further demonstrate that vulval cell terminal differentiation can be uncoupled from associated changes in vulval cell division planes.

The role of lin-22, a hairy/enhancer of split homolog, in patterning the peripheral nervous system of C. elegans

Development ◽  
1997 ◽  
Vol 124 (15) ◽  
pp. 2875-2888 ◽  
Author(s):  
L.A. Wrischnik ◽  
C.J. Kenyon
Keyword(s):  
Stem Cell ◽  
Regulatory Gene ◽  
Epidermal Cells ◽  
Body Axis ◽  
Wild Type ◽  
Hox Gene ◽  
C Elegans ◽  
Cell Divisions ◽  
Body Regions ◽  
Stem Cell Divisions

In C. elegans, six lateral epidermal stem cells, the seam cells V1-V6, are located in a row along the anterior-posterior (A/P) body axis. Anterior seam cells (V1-V4) undergo a fairly simple sequence of stem cell divisions and generate only epidermal cells. Posterior seam cells (V5 and V6) undergo a more complicated sequence of cell divisions that include additional rounds of stem cell proliferation and the production of neural as well as epidermal cells. In the wild type, activity of the gene lin-22 allows V1-V4 to generate their normal epidermal lineages rather than V5-like lineages. lin-22 activity is also required to prevent additional neurons from being produced by one branch of the V5 lineage. We find that the lin-22 gene exhibits homology to the Drosophila gene hairy, and that lin-22 activity represses neural development within the V5 lineage by blocking expression of the posterior-specific Hox gene mab-5 in specific cells. In addition, in order to prevent anterior V cells from generating V5-like lineages, wild-type lin-22 gene activity must inhibit (directly or indirectly) at least five downstream regulatory gene activities. In anterior body regions, lin-22(+) inhibits expression of the Hox gene mab-5. It also inhibits the activity of the achaete-scute homolog lin-32 and an unidentified gene that we postulate regulates stem cell division. Each of these three genes is required for the expression of a different piece of the ectopic V5-like lineages generated in lin-22 mutants. In addition, lin-22 activity prevents two other Hox genes, lin-39 and egl-5, from acquiring new activities within their normal domains of function along the A/P body axis. Some, but not all, of the patterning activities of lin-22 in C. elegans resemble those of hairy in Drosophila.

scholarly journals Hematopoietic Cell Fate and the Initiation of Leukemic Properties in Primitive Primary Human Cells Are Influenced by Ras Activity and Farnesyltransferase Inhibition

2004 ◽  
Vol 24 (16) ◽  
pp. 6993-7002 ◽  
Author(s):  
Craig Dorrell ◽  
Katsuto Takenaka ◽  
Mark D. Minden ◽  
Robert G. Hawley ◽  
John E. Dick
Keyword(s):  
Cell Fate ◽  
Myeloid Cell ◽  
Early Event ◽  
Ras Signaling ◽  
Human Leukemia ◽  
Ras Pathway ◽  
Hematopoietic Malignancies ◽  
Ras Activation ◽  
Elevated Frequency ◽  
High Level

ABSTRACT The Ras pathway transduces divergent signals determining normal cell fate and is frequently activated in hematopoietic malignancies, but the manner in which activation contributes to human leukemia is poorly understood. We report that a high level of activated H-Ras signaling in transduced primary human hematopoietic progenitors reduced their proliferation and enhanced monocyte/macrophage differentiation. However, the exposure of these cells to a farnesyltransferase inhibitor and establishment of a moderate level of Ras activity showed increased proliferation, an elevated frequency of primitive blast-like cells, and progenitors with enhanced self-renewal capacity. These results suggest that the amplitude of Ras pathway signaling is a determinant of myeloid cell fate and that moderate Ras activation in primitive hematopoietic cells can be an early event in leukemogenesis.

Patterning of the C. elegans 1 degrees vulval lineage by RAS and Wnt pathways

Development ◽  
2000 ◽  
Vol 127 (23) ◽  
pp. 5047-5058 ◽  
Author(s):  
M. Wang ◽  
P.W. Sternberg
Keyword(s):  
Short Range ◽  
Precursor Cell ◽  
Ras Signaling ◽  
Cell Fates ◽  
C Elegans ◽  
Asymmetric Divisions ◽  
Anchor Cell ◽  
Wnt Pathways ◽  
Vulval Precursor Cell ◽  
Proper Orientation

In C. elegans, the descendants of the 1 degrees vulval precursor cell (VPC) establish a fixed spatial pattern of two different cell fates: E-F-F-E. The two inner granddaughters attach to the somatic gonadal anchor cell (AC) and generate four vulF cells, while the two outer granddaughters produce four vulE progeny. zmp-1::GFP, a molecular marker that distinguishes these two fates, is expressed in vulE cells, but not vulF cells. We demonstrate that a short-range AC signal is required to ensure that the pattern of vulE and vulF fates is properly established. In addition, signaling between the inner and outer 1 degrees VPC descendants, as well as intrinsic polarity of the 1 degrees VPC daughters, is involved in the asymmetric divisions of the 1 degrees VPC daughters and the proper orientation of the outcome. Finally, we provide evidence that RAS signaling is used during this new AC signaling event, while the Wnt receptor LIN-17 appears to mediate signaling between the inner and outer 1 degrees VPC descendants.

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