Sengupta P et al. (2011) Curr Biol "Cellular reprogramming: chromatin puts on the brake."

Sengupta P, Schedl T

[Curr Biol, 2011]

Directed reprogramming of differentiated cells allows the generation of specific cell types for therapeutics and can provide unexpected insights into development. A recent study demonstrates that efficient reprogramming of Caenorhabditis elegans germ cells into neurons can be achieved by knocking down a histone chaperone gene and ectopic expression of a terminal selector transcription factor.

Sengupta P (1997) Semin Cell Dev Biol "Cellular and molecular analyses of olfactory behavior in C. elegans."

Sengupta P

[Semin Cell Dev Biol, 1997]

C. elegans responds to and discriminates among a large number of volatile and water-soluble chemicals using a few defined chemosensory neurons. The functions of individual sensory neurons have been defined by cell killing experiments, and genes required for responses to subsets of chemicals have been identified. C. elegans has several large families of putative chemosensory receptor genes, and one of these genes has been demonstrated to encode a receptor for a specific odorant. Current work is aimed at identifying additional components of chemosensory neuron development and function.

Sengupta P (2017) PLoS Biol "Cilia and sensory signaling: The journey from "animalcules" to human disease."

Sengupta P

[PLoS Biol, 2017]

Nearly all cell types in mammals contain cilia, small rod-like or more elaborate structures that extend from the cell surface. Cilia house signaling proteins that allow the cell to sample their environment and respond appropriately. Mutations in ciliary genes alter the functions of a broad range of cell and tissue types, including sensory and central neurons, and underlie a collection of heterogeneous human disorders called ciliopathies. Here, I highlight the critical contributions of nearly three centuries of research in diverse organisms to our current knowledge of cilia function in sensory signaling and human disease.

Sengupta P et al. (1993) Ciba Foundation Symposium "The cellular and genetic basis of olfactory responses in Caenorhabditis elegans."

Dwyer ND, Sengupta P, Bargmann CI, Kimmel BE, Colbert HA

[Ciba Foundation Symposium, 1993]

The small soil nematode Caenorhabditis elegans has only 302 neurons in its entire nervous system, so it is possible to analyse the functions of individual neurons in the animal's behaviour. We are using behavioural, cellular and genetic analyses of chemotactic responses to find out how olfactory behaviour patterns are generated and regulated. Single chemosensory neurons in C. elegans can recognize several different attractive odorants that are distinguished by the animal. Distinct sets of chemosensory neurons detect high and low concentrations of a single odorant. Odorant responses adapt after prolonged exposure to an odorant; this adaptation is odorant specific and reversible. Mutants with defects in odorant responses have been identified. Some genes appear to be necessary for the development or function of particular kinds of sensory neurons. Other genes have effects that suggest that they participate in odorant reception or signal transduction.

Sengupta P et al. (1996) Cell "odr-10 encodes a seven transmembrane domain olfactory receptor required for responses to the odorant diacetyl."

Chou JH, Sengupta P, Bargmann CI

[Cell, 1996]

Olfactory signaling is initiated by interactions between odorants and olfactory receptors. We show that the C. elegans odr-10 gene is likely to encode a receptor for the odorant diacetyl. odr-10 mutants have a specific defect in chemotaxis to diacetyl, one of several odorants detected by the AWA olfactory neurons. odr-10 encodes a predicted seven transmembrane domain receptor; a green fluorescent protein-tagged Odr-10 protein is localized to the AWA sensory cilia. odr-10 expression is regulated by odr-7, a transcription factor implicated in AWA sensory specification. Expression of odr-10 from a heterologous promoter directs behavioral responses to diacetyl, but not to another odorant detected by the AWA neurons. These results provide functional evidence for a specific interaction between an olfactory receptor protein and its odorant ligand.

Sengupta P et al. (1994) Cell "The C. elegans gene odr-7 encodes an olfactory-specific member of the nuclear receptor superfamily."

Colbert HA, Sengupta P, Bargmann CI

[Cell, 1994]

Olfactory discrimination is achieved through the action of olfactory neurons with diverse chemical specificities. In C. elegans, at least ten different types of chemosensory neurons respond to different chemicals. The odr-7 gene is required for the function of one pair of chemosensory neurons called AWA neurons. odr-7 null mutants fail to respond to all odorants detected by the AWA neurons, while a missense mutation in odr-7 causes a specific defect in one odorant response. odr-7 encodes a protein with similarity to the DNA-binding domain of the nuclear receptor genes; it is expressed predominantly in the AWA neurons. odr-7 may regulate the expression of olfactory signaling molecules that define a single type of olfactory

Goodman MB et al. (2019) Genetics "How Caenorhabditis elegans Senses Mechanical Stress, Temperature, and Other Physical Stimuli."

Sengupta P, Goodman MB

[Genetics, 2019]

<i>Caenorhabditis elegans</i> lives in a complex habitat in which they routinely experience large fluctuations in temperature, and encounter physical obstacles that vary in size and composition. Their habitat is shared by other nematodes, by beneficial and harmful bacteria, and nematode-trapping fungi. Not surprisingly, these nematodes can detect and discriminate among diverse environmental cues, and exhibit sensory-evoked behaviors that are readily quantifiable in the laboratory at high resolution. Their ability to perform these behaviors depends on &lt;100 sensory neurons, and this compact sensory nervous system together with powerful molecular genetic tools has allowed individual neuron types to be linked to specific sensory responses. Here, we describe the sensory neurons and molecules that enable <i>C. elegans</i> to sense and respond to physical stimuli. We focus primarily on the pathways that allow sensation of mechanical and thermal stimuli, and briefly consider this animal's ability to sense magnetic and electrical fields, light, and relative humidity. As the study of sensory transduction is critically dependent upon the techniques for stimulus delivery, we also include a section on appropriate laboratory methods for such studies. This chapter summarizes current knowledge about the sensitivity and response dynamics of individual classes of <i>C. elegans</i> mechano- and thermosensory neurons from <i>in vivo</i> calcium imaging and whole-cell patch-clamp electrophysiology studies. We also describe the roles of conserved molecules and signaling pathways in mediating the remarkably sensitive responses of these nematodes to mechanical and thermal cues. These studies have shown that the protein partners that form mechanotransduction channels are drawn from multiple superfamilies of ion channel proteins, and that signal transduction pathways responsible for temperature sensing in <i>C. elegans</i> share many features with those responsible for phototransduction in vertebrates.

Maurya AK et al. (2021) Curr Biol "xbx-4, a homolog of the Joubert syndrome gene FAM149B1, acts via the CCRK and RCK kinase cascade to regulate cilia morphology."

Sengupta P, Maurya AK

[Curr Biol, 2021]

Primary cilia are microtubule (MT)-based organelles that mediate sensory functions in multiple cell types. Disruption of cilia structure or function leads to a diverse collection of diseases termed ciliopathies.^1-3 The highly conserved CCRK and RCK kinases (ICK/MOK/MAK) negatively regulate cilia length and structure in Chlamydomonas, C.elegans, and mammalian cells.^4-10 How the activity of this kinase cascade is tuned to precisely regulate cilia architecture is unclear. Mutations in the Domain of Unknown Function 3719 (DUF3719)-containing protein FAM149B1 have recently been shown to elongate cilia via unknown mechanisms and result in the ciliopathy Joubert syndrome.¹¹ Here we identify XBX-4, a DUF3719-containing protein related to human FAM149B1, as a regulator of the DYF-18 CCRK and DYF-5 MAK kinase pathway in C.elegans. As in dyf-18 and dyf-5 mutants,¹⁰ sensory neuron cilia are elongated in xbx-4 mutants and exhibit stabilized axonemal MTs. XBX-4 promotes DYF-18 CCRK function to regulate localization and function of DYF-5 MAK. We find that Joubert syndrome-associated mutations in the XBX-4 DUF3719 domain also elongate cilia in C.elegans. Our results identify a new metazoan-specific regulator of this highly conserved kinase pathway and suggest that FAM149B1 may similarly act via the CCRK/RCK kinase pathway to regulate ciliary homeostasis in humans.

Hill TJ et al. (2024) Proc Natl Acad Sci U S A "Feedforward and feedback mechanisms cooperatively regulate rapid experience-dependent response adaptation in a single thermosensory neuron type."

Sengupta P, Hill TJ

[Proc Natl Acad Sci U S A, 2024]

Sensory adaptation allows neurons to adjust their sensitivity and responses based on recent experience. The mechanisms that mediate continuous adaptation to stimulus history over seconds- to hours-long timescales, and whether these mechanisms can operate within a single sensory neuron type, are unclear. The single pair of AFD thermosensory neurons in <i>Caenorhabditis elegans</i> exhibits experience-dependent plasticity in their temperature response thresholds on both minutes- and hours-long timescales upon a temperature upshift. While long-term response adaptation requires changes in gene expression in AFD, the mechanisms driving rapid response plasticity are unknown. Here, we show that rapid thermosensory response adaptation in AFD is mediated via cGMP and calcium-dependent feedforward and feedback mechanisms operating at the level of primary thermotransduction. We find that either of two thermosensor receptor guanylyl cyclases (rGCs) alone is sufficient to drive rapid adaptation, but that each rGC drives adaptation at different rates. rGC-driven adaptation is mediated in part via phosphorylation of their intracellular domains, and calcium-dependent feedback regulation of basal cGMP levels via a neuronal calcium sensor protein. In turn, cGMP levels feedforward via cGMP-dependent protein kinases to phosphorylate a specific subunit of the cGMP-gated thermotransduction channel to further regulate rapid adaptation. Our results identify multiple molecular pathways that act in AFD to ensure rapid adaptation to a temperature change and indicate that the deployment of both transcriptional and nontranscriptional mechanisms within a single sensory neuron type can contribute to continuous sensory adaptation.

Loo TW et al. (2013) Biochemistry "A salt bridge in intracellular loop 2 is essential for folding of human p-glycoprotein."

Clarke DM, Loo TW

[Biochemistry, 2013]

There is no high-resolution structure of the human P-glycoprotein (P-gp, ABCB1) drug pump. Homology models based on the crystal structures of mouse and Caenorhabditis elegans P-gps show extensive contacts between intracellular loop 2 (ICL2, in the first transmembrane domain) and the second nucleotide-binding domain. Human P-gp modeled on these P-gp structures yields different ICL2 structures. Only the model based on the C. elegans P-gp structure predicts the presence of a salt bridge. We show that the Glu256-Arg276 salt bridge was critical for P-gp folding.