Genomic cis-Regulatory Architecture and trans-Acting Regulators of a Single Interneuron-Specific Gene Battery in C. elegans

The vulval development of Caenorhabditis elegans provides an opportunity to investigate genetic networks that control gene expression during organogenesis. During the fourth larval stage (L4), seven vulval cell types are produced, each of which executes a distinct gene expression program. We analyze how the expression of cell-type-specific genes is regulated. Ras and Wnt signaling pathways play major roles in generating the spatial pattern of cell types and regulate gene expression through a network of transcription factors. One transcription factor (lin-29) primarily controls the temporal expression pattern. Other transcription factors (lin-11, cog-1, and egl-38) act in combination to control cell-typespecific gene expression. The complexity of the network arises in part because of the dynamic nature of gene expression, in part because of the presence of seven cell types, and also because there are multiple regulatory paths for gene expression within each cell type.organogenesis ͉ signaling pathways ͉ transcription D evelopmental events are driven by spatially and temporally regulated gene expression. Understanding how complex patterns of expression are produced is therefore a critical part of deciphering mechanisms of development. In general, intercellular signaling mechanisms interact with a network of transcription factors to generate cell-type-specific patterns of gene expression. The late stage of Caenorhabditis elegans vulval development offers a useful model in which to study this process. During this period of vulval development, seven distinct cell types are produced that express unique combinations of genes. Over the last several years, a number of genes were discovered that are expressed in cell-type and stage-specific patterns in the vulva, and several transcription factors were found to regulate these genes. In this paper, we synthesize and extend our current knowledge of this genetic network.The C. elegans vulva connects the uterine lumen to the outside, allowing for passage of sperm and fertilized eggs (1). Vulval cells are generated postembryonically from precursor cells P3.p P4.p, P5.p, P6.p, P7.p, and P8.p [also called vulval precursor cells (VPC)]. During the mid-third larval (L3) stage, EGF and Notch signaling induces the middle three VPCs (P5.p, P6.p, and P7.p) to adopt vulval fates, whereas P3.p, P4.p, and P8.p fuse with the hypodermal syncytium, hyp7 (2-6).During the late-L3 to the early-L4 stage, P5.p, P6.p, and P7.p undergo two or three rounds of cell division to produce 22 nuclei (7) (Fig. 1A). These nuclei are in cells of seven types (vulA, vulB1, vulB2, vulC, vulD, vulE, and vulF), as evidenced by subsequent morphogenetic movements and by the pattern of gene expression (8, 9) (Fig. 1B). The seven cell types that are present in the adult vulva represent specializations within the general epithelial cell class. These cells exhibit cell-type general features; for example, each expresses ajm-1, a component of the apical junction that connects neighboring cells in epithelial tissues (8)....

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“…43). However, our understanding of vulval development is still limited, relative to the number of cell types (34) and Kirouac and Sternberg (33).…”

Section: Resultsmentioning

confidence: 99%

Transcriptional network underlying Caenorhabditis elegans vulval development

Inoué

Wang

Ririe

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…with the insulin/IGF-1 pathway (Oh et al, 2005); the jnk-1 gene is expressed in AIY (Wenick and Hobert, 2004).…”

Section: Discussionmentioning

confidence: 99%

Aging-Dependent and -Independent Modulation of Associative Learning Behavior by Insulin/Insulin-Like Growth Factor-1 Signal inCaenorhabditis elegans

Murakami¹,

Bessinger²,

Hellmann³

et al. 2005

J. Neurosci.

114

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Mutations in the insulin/IGF-1 neuroendocrine pathway extend lifespan and affect development, metabolism, and other biological processes in Caenorhabditis elegans and in other species. In addition, they may play a role in learning and memory. Investigation of the insulin/IGF-1 pathway may provide clues for the prevention of age-related declines in cognitive functions. Here, we examined the effects of the life-extending (Age) mutations, such as the age-1 (phosphatidylinositol 3-OH kinase) and daf-2 (insulin/IGF-1 receptor) mutations, on associative learning behavior called isothermal tracking. This thermotaxis learning behavior associates paired stimuli, temperature, and food. The age-1 mutation delayed the age-related decline of isothermal tracking, resulting in a 210% extension of the period that ensures it. The effect is dramatic compared with the extension of other physiological health spans. In addition, young adults of various Age mutants (age-1, daf-2, clk-1, and eat-2) showed increased consistency of temperature-food association, which may be caused by a common feature of the mutants, such as the secondary effects of life extension (i.e., enhanced maintenance of neural mechanisms). The age-1 and daf-2 mutants but not the other Age mutants showed an increase in temperature-starvation association through a different mechanism. Increased temperature-food association of the daf-2 mutant was dependent on neuronal Ca 2ϩ -sensor ncs-1, which modulates isothermal tracking in the AIY interneuron. Interestingly, mutations in the daf-7 TGF␤ gene, which functions in parallel to the insulin/IGF-1 pathway, caused deficits in acquisition of temperature-food and temperature-starvation association. This study highlights roles of the Age mutations in modulation of certain behavioral plasticity.

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“…A broad battery of genes that defines AIY identity shares a small cisregulatory motif, called the AIY motif (Table 1), which, like the ASE motif, is required and sufficient to instruct gene expression in AIY (9). Like the ASE motif, the AIY motif commonly occurs in single copy in the vicinity of AIYexpressed genes.…”

Section: Aiy Interneuronsmentioning

confidence: 99%

“…Like the ASE motif, the AIY motif commonly occurs in single copy in the vicinity of AIYexpressed genes. The AIY motif is synergistically activated by a dimer of two homeodomain proteins, the TTX-3 LIM homeodomain protein and the CEH-10 Paired-type homeodomain protein (9). Each of these factors is expressed in a few neurons, but their expression exclusively overlaps in the AIY neuron class, thereby making them, as is the case for CEH-1, a unique identifier for AIY identity (10).…”

Section: Aiy Interneuronsmentioning

confidence: 99%

Regulatory logic of neuronal diversity: Terminal selector genes and selector motifs

Hobert

2008

Proc. Natl. Acad. Sci. U.S.A.

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263

284

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Individual neuronal cell types are defined by the expression of unique batteries of terminal differentiation genes. The elucidation of the cis-regulatory architecture of several distinct, single neuron type-specific gene batteries in Caenorhabditis elegans has revealed a strikingly simple cis-regulatory logic, in which small cis-regulatory motifs are activated in postmitotic neurons by autoregulating transcription factors (TFs). Loss of the TFs results in the loss of the identity of the individual neuron type. I propose to term these TFs ''terminal selector genes'' and their cognate cis-regulatory target sites ''terminal selector motifs.'' Terminal selector genes assign individual neuronal identities by directly controlling the expression of downstream, terminal differentiation genes and act in specific regulatory network configurations. The simplicity of the cis-regulatory logic on which the terminal selector gene concept is based may contribute to the evolvability of neuronal diversity.

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Genomic cis-Regulatory Architecture and trans-Acting Regulators of a Single Interneuron-Specific Gene Battery in C. elegans

Cited by 218 publications

References 43 publications

Transcriptional network underlying Caenorhabditis elegans vulval development

Transcriptional network underlying Caenorhabditis elegans vulval development

Aging-Dependent and -Independent Modulation of Associative Learning Behavior by Insulin/Insulin-Like Growth Factor-1 Signal inCaenorhabditis elegans

Regulatory logic of neuronal diversity: Terminal selector genes and selector motifs

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