Research
Our lab addresses two overarching questions:
How do glia influence nervous system development and function?
How is programmed cell death controlled?
We generally use the nematode C. elegans as our model system, although we have been known to stray. C. elegans offers a wonderfully tractable experimental setting, as the hermaphrodite has only 959 somatic cells of which 302 are neurons and 56 are glial cells. All cells arise from identical patterns of cell division following oocyte fertilization, with a reproducible spatial arrangemnt across individuals. The identities of dying cells and their times of death in development are also essentially invariant
We discovered that glia are not needed to keep neurons alive, allowing us to identify multiple ways in which they influence neuron morphogenesis and function. We also discovered novel non-apoptotic pathways driving cell death in this animal.
Glia in nervous system development and function
Shaping and pruning neurons
Glia actively set and modulate the shapes of sensory neuron dendritic endings, thereby affecting C. elegans behavior. For example, we found that a glial potassium/chloride transporter controls receptive-ending shape through chloride inhibition of a neuronal receptor guanylate cyclase. Glia also prune thermosensory neuron endings by controlled phagocytosis, and both functions set thermotaxis behavior. As another example, the Prospero-like factor PROS-1 directs expression of a glial secretome governing neuron shape and function, and is required for multiple sensory modalities.
Singhvi et al. 2016 · Wallace et al. 2016 · Procko et al. 2011 · Procko et al. 2012 · Raiders et al. 2021 · Huang et al. 2020 · Procko & Shaham 2010
Sensory organ function and structure
Glia are required for sense organs to work at all: removing them leaves neurons intact but functionally blind. We study how glia and neurons build the compartments of a sense organ together, and the channels and morphogenesis genes that underlie this.
Bacaj et al. 2008 · Wang et al. 2008 · Han et al. 2013 · Wang et al. 2017 · Perens & Shaham 2005 · Oikonomou et al. 2011 · Oikonomou et al. 2012
Monitoring and protecting neurons
Glia keep watch over the neurons they enwrap. We recently showed that glia detect the loss of structural integrity in a neuron’s dendritic substructure and mount a protective response. In separate studies we showed that glial detoxifying-enzyme programs protect the animal from environmental threats.
Controlling behavior
Because we can silence or remove individual glia, we can ask how they shape behavior. Glia modulate a circuit that suppresses movement during sleep; a glial GPCR drives stress-induced plasticity supporting adaptive behavior; and glial regulation of glutamate spillover, through the astrocytic GLT-1 glutamate transporter and a neuronal mGluR5-related receptor MGL-2, controls repetitive behavior — with possible relevance to repetitive behaviors in humans.
Katz et al. 2018 · Katz et al. 2019 · Lee et al. 2020 · Peliti et al. 2013
Dendrite growth and identity
We discovered how a sensory dendrite gets its length: DEX-1 and DYF-7 anchor the dendrite tip while the cell body migrates away, stretching the dendrite into place. We also continue to study how neurons and glia acquire their molecular identities.
Heiman & Shaham 2009 · Heiman & Shaham 2010 · Mizeracka et al. 2021 · Shaham & Bargmann 2002 · Clark et al. 2010
Building the brain, and the diversity of glia
During development, the four CEPsh glia initiate assembly of the nerve ring, the animal’s central neuropil (brain), through a noncanonical Chimaerin–Furin axon-guidance pathway. We identified the transcriptomes of CEPsh glia during this time period to identify novel regulators of glial functions. We are also defining how distinct classes of glia acquire and keep their identity, including mesodermal glia specified by the Forkhead factor LET-381/FoxF and its target UNC-30/Pitx2, which also ensheathe the nerve ring and share molecular features with vertebrate neurovascular unit cells.
Rapti et al. 2017 · Stefanakis et al. 2024 · Stefanakis et al. 2025 · Yoshimura et al. 2008 · Rashid et al. 2022 · review: Singhvi, Shaham & Rapti 2024 · review: Singhvi & Shaham 2019
Cell death mechanisms and control
The decision and timing to die
Building a nervous system requires eliminating specific cells at specific moments. We study what marks a cell for death and how the killing machinery is switched on at the right time — including transcriptional induction of the CED-3 caspase and the upstream regulators that set the timing of death.
Maurer et al. 2007 · Schumacher et al. 2005 · Jiang et al. 2021 · Shaham et al. 1999 · Shaham & Horvitz 1996 · review: Horowitz & Shaham 2024
A non-apoptotic death program
Studying the death of the male linker cell, we defined a morphologically distinct, caspase-independent form of programmed cell death whose features also appear in the developing vertebrate nervous system (LCD, linker-cell type death). We dissect how this death is executed and how the dying cell is cleared. In a separate set of studies, we defined novel mechanisms required for eliminating a neuron-like, morphologically complex cell, using a fusogen, EFF-1, and a Kinesin-3 dependent mitochondria transport process.
Abraham et al. 2007 · Blum et al. 2012 · Malin et al. 2016 · Kinet et al. 2015 · Kutscher et al. 2018 · Ghose et al. 2018 · Sharmin et al. 2025 · Schwendeman & Shaham 2016 · review: Kutscher & Shaham 2017
Links to human disease
The LCD program is controlled in part by a polyglutamine-repeat protein, raising the possibility that misregulation of a developmental death pathway contributes to polyglutamine (polyQ) neurodegenerative disease. Mutations in TIR-1/Sarm and BTBD-2 suggest possible relatedness of LCD to axon degeneration programs. F-box protein degradation regulators connect worm biology to human lymphoma.
Technology and tool development
Temporal control of cell-specific gene expression
Cell-specific promoters allow only spatial control of transgene expression. We developed a method, using cell-specific rescue of heat-shock factor-1 (hsf-1) mutants, that allows spatial and temporal regulation of transgene expression. We demonstrated the utility of this method for timed reporter gene expression and for temporal studies of gene function.
An infrared laser cell-specific gene induction/cell ablation system
We developed a method, using an infrared laser, for reproducible heat-dependent gene expression in small sublineages (one to four cells) without radiation damage. We demonstrated use of our system to label and track single neurons during early nervous system assembly.
A scanning-mode SPIM microscope
Single plane illumination microscopy (SPIM) is an alternative to confocal microscopy that can rapidly collect z-stacks. We built a scanning version of this microscope useful in the study of moving C. elegans embryos.
Aligning C. elegans embryos
We developed automated algorithms for spatiotemporal alignments of C. elegans embryos from pre-morphogenesis to motor-activity initiation. We used sparsely-labeled green-fluorescent nuclei and a pan-nuclear red-fluorescent reporter to register consecutive imaging time points and compare embryos. Using our method, we monitored early assembly of the nerve-ring (brain) neuropil.
Optimizing genetic screens
In genetic screens, the number of mutagenized gametes examined is an important parameter for evaluating screen progress. We employed a modified binomial strategy to obtain a general expression for the number of mutagenized gametes examined in a genetic screen and used this expression to develop algorithms for calculating optimal screen parameters.
galign mutation calling software
We developed a tool to identify polymorphisms between test and reference genomes. The alignment tool compares parsed sequence reads to parsed reference genome sequences and the output is geared towards immediate application, displaying polymorphism locations, nucleotide changes, and predicted amino-acid changes, where relevant.
A long-term imaging platform for C. elegans
Long-term studies of C. elegans larval development traditionally require tedious manual observations. We developed a microfluidic device to simultaneously follow development of ten larvae at high spatiotemporal resolution from hatching to adulthood (3 days). We combined Nomarski and multichannel fluorescence microscopy to study processes such as cell-fate specification, cell death, transdifferentiation, and neuronal arborization throughout post-embryonic development.
The complete list of the lab’s work, with PDFs, is on the Publications page. To discuss joining the lab or a collaboration, see Contact.