The Sengupta lab is interested in exploring the complex interactions between an animal and its environment. Animals must recognize and respond to multiple, complex environmental signals, and translate this information into the appropriate behavioral and developmental responses. What are the molecules, signaling pathways and neuronal circuits that allow animals to respond to environmental cues? Moreover, how does a memory of past experience modify the animal's response?

We use molecular genetic approaches to study these issues in the model organism Caenorhabditis elegans. C. elegans has a number of advantages for studying neuronal development and function.

• C. elegans exhibits complex, experience-dependent behaviors that can be readily quantified.
• Molecules required for different behaviors can be easily identified using forward and reverse genetic approaches.
• All modern genomics and proteomics-based tools can be applied in C. elegans, allowing us to identify and analyze sets of molecules required for specific processes.
• The nervous system of C. elegans consists of only 302 neurons, each of which can be easily identified.
• The connectivities of each neuron have been anatomically mapped, allowing us to characterize the circuits underlying specific behaviors.
• Individual neuron function can be monitored and manipulated using both genetic and physiological tools.
• Finally, C. elegans is easy to work with in practice - animals have a rapid lifecycle, can be asily grown in the lab and strains can be frozen at -80°C.
• More information about C. elegans can be found at WormBase.

Ongoing projects in the lab are aimed at addressing three broad questions:

Neuronal Development |
Chemosensory Signal Transduction, and Experience-dependent Modulation of Behavior |
Thermotaxis

Like other animals, C. elegans is attracted to, or avoids, subsets of chemicals. Chemicals are recognized by a small number of chemosensory neurons, each of which expresses a defined subset of signaling genes such as chemoreceptors, and exhibits a distinct cell type-specific morphology.

i) Neuronal specification: We are investigating the molecular mechanisms that confer cell type-specific properties onto each of these sensory neuron types. We have identified transcription factor cascades that are essential for the expression of cell-specific signaling genes. We are also dissecting the cis-regulatory mechanisms that drive gene expression in defined cell types.

(A) Examples of amphid ciliated sensory neurons: channel and wing (ASH and AWB, respectively). (B) The forked ciliary morphology of the AWB olfactory neuron type visualized via cell-specific GFP expression (from Mukhopadhyay et al., 2008)

ii) Cilia development: Several chemosensory neuron types exhibit highly specialized ciliary structures that are essential for their unique sensory functions. We are exploring how these specialized cilia develop and are maintained. In the last few years, it has become evident that virtually every cell type in a vertebrate is ciliated, and that ciliary dysfunction contributes to a large number of disorders such as Bardet-Biedl syndrome, polycystic kidney disease and retinopathies. Cilia are formed via highly conserved mechanisms, and C. elegans has proved to be an excellent model organism for studying cilia development. However, little is known about how specialized cilia are generated. We have identified a transcription factor required for the formation of one specialized cilia type, and have also shown that sensory activity plays a role in the maintenance of cilia structure. We are currently using a genetics and proteomics-based approach to identify additional molecules and mechanisms required for the generation and maintenance of these diverse cilia structures. Given the high degree of conservation in ciliary developmental mechanisms across phyla, we fully expect that our work will be directly relevant in higher organisms.

Funding: NIH R37 MERIT Award

Related publications from our lab on this topic since 2005 (a full list can be found here):

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We are interested in identifying the signaling pathways by which animals respond to environmental chemicals. For instance, C. elegans monitors the presence of other nematodes in its environment by monitoring the concentration of dauer pheromone, a complex mixture of fatty acids that is produced by these animals at all developmental stages. High concentrations of dauer pheromone signal overcrowding and competition for resources, and triggers a number of developmental and behavioral changes.

i) Pheromone signaling pathways: We have recently identified receptors for dauer pheromone, and have shown that complex, intracellular signaling pathways are required for pheromone-regulated developmental and behavioral responses. We are further characterizing these signaling pathways, and exploring how these pathways are used to communicate within and among nematode species. This information may be useful to combat infection by parasitic nematodes.

ii) Environmental regulation of chemoreceptor genes: We have shown that a simple mechanism by which past experience can modulate C. elegans behavior is via dynamic regulation of expression of chemoreceptor genes. We have identified signaling cascades that regulate chemoreceptor gene expression, and are investigating how information about the environment and internal metabolic state is integrated to modulate chemoreceptor gene expression and behaviors such as feeding.

An osm-9p::gfp fusion gene is expressed in three neuron types in control adult animals, but only in two neuron types in adult animals that passed through the alternate dauer developmental stage. (S.E. Hall)

iii) A cellular memory of developmental history: We have recently found that C. elegans retains a memory of its developmental history. Thus, animals exposed to specific environmental conditions as larvae exhibit distinct gene expression patterns and behaviors as adults. Preliminary experiments suggest that this memory is maintained via epigenetic mechanisms such as altered chromatin modification patterns. These results are intriguing, since work in mammals has implicated similar epigenetic regulatory mechanisms in governing adult behaviors based on prenatal or early postnatal experience. We are currently identifying the molecular mechanisms required for the formation of this cellular memory.

Funding: NSF, HFSP

Related publications from our lab on this topic since 2005 (a full list can be found here):

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Although much is known about how animals respond to sensory stimuli such as light and chemicals, the neuronal and molecular mechanisms underlying thermosensation is poorly understood. C. elegans exhibits a remarkably complex response to temperature, such that the behavior of C. elegans on a thermal gradient is dictated by a memory of its cultivation temperature. This experimental paradigm provides an excellent opportunity to understand how a behavior is generated from the level of single genes to the output of a neuronal circuit(s).

i) Molecules required for thermosensory signal transduction: We are using genetic and genomic approaches to identify putative thermoreceptors and signaling molecules required for transduction of thermal information.

ii) Neuronal circuits required for thermosensation: We are identifying the components of the thermosensory circuit. Using genetically encoded calcium sensors, we are also monitoring neuronal activity in response to thermosensory cues.

iii) Role of past experience in modulating thermosensory behaviors: We are investigating how past thermal and feeding experience modulates thermosensory behaviors.

Funding: NIH R01

Related publications from our lab on this topic since 2005 (a full list can be found here):

[Top]

• Current Funding
  • NIH R37
  • NIH R01
  • NSF
  • HFSP
• Past Funding
  • Searle Scholars Program
  • Alfred P. Sloan Foundation
  • Whitehall Foundation
  • Packard Foundation
  • The Medical Foundation