William Wadsworth | Rutgers, The State University of New Jersey (original) (raw)

Research Papers by William Wadsworth

Current Opinion in Neurobiology, 1992

Genetics, 2011

Gradients of acetylcholine can stimulate growth cone turning when applied to neurons grown in cul... more Gradients of acetylcholine can stimulate growth cone turning when applied to neurons grown in culture, and it has been suggested that acetylcholine could act as a guidance cue. However, the role acetylcholine plays in directing axon migrations in vivo is not clear. Here, we show that acetylcholine positively regulates signaling pathways that mediate axon responses to guidance cues in Caenorhabditis elegans. Mutations that disrupt acetylcholine synthesis, transportation, and secretion affect circumferential axon guidance of the AVM neuron and in these mutants exogenously supplied acetylcholine improves AVM circumferential axon guidance. These effects are not observed for the circumferential guidance of the DD and VD motor neuron axons, which are neighbors of the AVM axon. Circumferential guidance is directed by the UNC-6 (netrin) and SLT-1 (slit) extracellular cues, and exogenously supplied acetylcholine can improve AVM axon guidance in mutants when either UNC-6-or SLT-1-induced signaling is disrupted, but not when both signaling pathways are perturbed. Not in any of the mutants does exogenously supplied acetylcholine improve DD and VD axon guidance. The ability of acetylcholine to enhance AVM axon guidance only in the presence of either UNC-6 or SLT-1 indicates that acetylcholine potentiates UNC-6 and SLT-1 guidance activity, rather than acting itself as a guidance cue. Together, our results show that for specific neurons acetylcholine plays an important role in vivo as a modulator of axon responses to guidance cues.

The Journal of Lipid Research, 2003

Caenorhabditis elegans requires sterol, usually supplied as cholesterol, but this is enzymaticall... more Caenorhabditis elegans requires sterol, usually supplied as cholesterol, but this is enzymatically modified, and different sterols can substitute. Sterol deprivation decreased brood size and adult growth in the first generation, and completely, reversibly, arrested growth as larvae in the second. After one generation of sterol deprivation, 10 ng/ml cholesterol allowed delayed laying of a few eggs, but full growth required 300 ng/ml. C. elegans synthesizes two unusual 4 ␣ -methyl sterols (4MSs), but each 4MS supported only limited growth as the sole sterol. However, addition of only 10 ng of cholesterol to 1,000 ng of 4MS restored full growth and egg-laying, suggesting that both a 4MS and an unmethylated sterol are required for development. Filipin stained sterols in only a few specific cells: the excretory gland cell, two amphid socket cells, two phasmid socket cells and, in males, spicule socket cells. Sterols were also present in the pharynx and in the intestine of feeding animals in a proximal-to-distal gradient.

Developmental Biology, 2006

Laminins are components of basement membranes that are required for morphogenesis, organizing cel... more Laminins are components of basement membranes that are required for morphogenesis, organizing cell adhesions and cell signaling. Studies have suggested that laminins function as a x h y g z heterotrimers in vivo. In C. elegans, there is only one laminin h gene, suggesting that it is required for all laminin functions. Our analysis is consistent with the role of the laminin h as a subunit of laminin heterotrimers; the same cells express the laminin a, h, and g subunits, the laminin h subunit localizes to all basement membranes throughout development, and secretion of the h subunit requires an a subunit. RNAi inhibition of the h subunit gene or of the other subunit genes causes an embryonic lethality phenotype. Furthermore, a distinctive set of phenotypes is caused by both viable laminin a and h partial loss-of-function mutations. These results show developmental roles for the laminin h subunit, and they provide further genetic evidence for the importance of heterotrimer assembly in vivo. D

How extracellular molecules influence the direction of axon guidance is poorly understood. The HS... more How extracellular molecules influence the direction of axon guidance is poorly understood. The HSN axon of Caenorhabditis elegans is guided towards a ventral source of secreted UNC-6 (netrin). The axon's outgrowth response to UNC-6 is mediated by the UNC-40 (DCC) receptor. We have proposed that in response to the UNC-6 molecule the direction of UNC-40mediated axon outgrowth is stochastically determined. The direction of guidance is controlled by asymmetric cues, including the gradient of UNC-6, that regulate the probability that UNC-40-mediated axon outgrowth is directed on average, over time, in a specific direction. Here we provide genetic evidence that a specialized extracellular matrix, which lies ventral to the HSN cell body, regulates the probability that UNC-40-mediated axon outgrowth will be directed ventrally towards the matrix. We show that mutations that disrupt the function of proteins associated with this matrix, UNC-52 (perlecan), UNC-112 (kindlin), VAB-19 (Kank), and UNC-97 (PINCH), decrease the probability of UNC-40-mediated axon outgrowth in the ventral direction, while increasing the probability of outgrowth in the anterior and posterior directions. Other results suggest that INA-1 (a integrin) and MIG-15 (NIK kinase) signaling mediate the response in HSN. Although the AVM axon also migrates through this matrix, the mutations have little effect on the direction of AVM axon outgrowth, indicating that responses to the matrix are cell-specific. Together, these results suggest that an extracellular matrix can regulate the direction of UNC-6 guidance by increasing the probability that UNC-40-mediated axon outgrowth activity will be oriented in a specific direction.

Neuron, 1996

Netrins are laminin-related proteins that guide circumferential migrations on the ectoderm. To un... more Netrins are laminin-related proteins that guide circumferential migrations on the ectoderm. To understand how netrin cues direct cell movements, we examined the expression of nematode netrin UNC-6 from embryo to adult. UNC-6 is expressed in 12 types of neuroglia and neurons, creating a hierarchy of netrin cues in the developing nervous system. Comparing gene expression pattern with in vivo phenotypes, we suggest how multiple netrin cues, each with a characteristic role, guide cells and axons during development. We also present the molecular analysis of selective loss-of-function and null alleles. The results indicate that the biological activities of netrins are mediated through distinct protein domains. Subtle mutations in domain VI can produce selective defects in both direction- and tissue-specific guidance. EGF-like module V-2 is essential for dorsal guidance activity; we infer this module is important for interactions between UNC-6 and the dorsal guidance receptor UNC-5.

Journal of Neurobiology, 1999

The nervous system of Caenorhabditis elegans comprises circumferential and longitudinal axon trac... more The nervous system of Caenorhabditis elegans comprises circumferential and longitudinal axon tracts. Netrin UNC-6 is required for the guidance of circumferential axon migrations and is expressed by ventral neuroglia and neurons in temporally and spatially regulated patterns. Migrating axons mediate the UNC-6 signal through the UNC-5 and UNC-40 receptors. It is thought that UNC-6 is secreted and becomes associated with basement membranes and cell surfaces to form gradients that direct circumferentially migrating axons toward or away from the ventral UNC-6 sources. Little is known about the effects of UNC-6 on longitudinally migrating axons. In unc-6, unc-5, and unc-40 null mutants, some longitudinal nerves are dorsally or ventrally misdirected. Furthermore, the organization of axons are disrupted within nerves. We show that cells ectopically expressing UNC-6 can redirect the migrations of some neighboring longitudinal axons, suggesting that the gradients postulated to direct circumferential migration also help specify the dorsoventral positions of these longitudinal nerves. We also manipulated the temporal and spatial expression pattern of UNC-6 by two different means. First, we removed the PVT midline neuron which expresses UNC-6 for a short time during axon outgrowths. Second, we expressed UNC-6 uniformly in the nervous system throughout development. The results suggest that changing UNC-6 expression patterns modify the distribution of the cue by providing new localized sources. This new guidance information is critical for organizing the axons of longitudinal nerves.

Current Biology, 2008

Axon migrations are guided by extracellular cues that induce asymmetric outgrowth activity in the... more Axon migrations are guided by extracellular cues that induce asymmetric outgrowth activity in the growth cone . Several intracellular signaling proteins have been implicated in the guidance response . However, how these proteins interact to generate asymmetric outgrowth activity is unknown. Here, we present evidence that in C. elegans, the CED-10/Rac1 GTPase binds to and causes asymmetric localization of MIG-10/lamellipodin, a protein that regulates actin polymerization and has outgrowth-promoting activity in neurons . Genetic analysis indicates that mig-10 and ced-10 function together to orient axon outgrowth. The RAPH domain of MIG-10 binds to activated CED-10/Rac1 and ced-10 function is required for the asymmetric localization of MIG-10 that occurs in response to the UNC-6/netrin guidance cue. We also show that asymmetric localization of MIG-10 in growth cones is associated with asymmetric concentrations of f-actin and microtubules. These results suggest that CED-10/Rac1 is asymmetrically activated in response to the UNC-6/netrin signal, thereby causing asymmetric recruitment of MIG-10/lamellipodin. We propose that the interaction between activated CED-10/Rac1 and MIG-10/lamellipodin triggers local cytoskeletal assembly and polarizes outgrowth activity in response to UNC-6/netrin.

Current Biology, 2006

Axon migrations are guided by extracellular cues that can act as repellants or attractants. Howev... more Axon migrations are guided by extracellular cues that can act as repellants or attractants. However, the logic underlying the manner through which attractive and repulsive responses are determined is unclear. Many extracellular guidance cues, and the cellular components that mediate their signals, have been implicated in both types of responses.Genetic analyses indicate that MIG-10/RIAM/lamellipodin, a cytoplasmic adaptor protein, functions downstream of the attractive guidance cue UNC-6/netrin and the repulsive guidance cue SLT-1/slit to direct the ventral migration of the AVM and PVM axons in C. elegans. Furthermore, overexpression of MIG-10 in the absence of UNC-6 and SLT-1 induces a multipolar phenotype with undirected outgrowths. Addition of either UNC-6 or SLT-1 causes the neurons to become monopolar. Moreover, the ability of UNC-6 or SLT-1 to direct the axon ventrally is enhanced by the MIG-10 overexpression. We also demonstrate that an interaction between MIG-10 and UNC-34, a protein that promotes actin-filament extension, is important in the response to guidance cues and that MIG-10 colocalizes with actin in cultured cells, where it can induce the formation of lamellipodia.We conclude that MIG-10 mediates the guidance of AVM and PVM axons in response to the extracellular UNC-6 and SLT-1 guidance cues. The attractive and repulsive guidance cues orient MIG-10-dependant axon outgrowth to cause a directional response.

UNC-6, a laminin-related protein, guides cell and pioneer axon migrations in C. elegans, Nov 1992

The unc-6 gene is required for the guidance of pioneer axons and migrating cells along the body w... more The unc-6 gene is required for the guidance of pioneer axons and migrating cells along the body wall in C. elegans. In mutants, dorsal and ventral migrations are disrupted, but longitudinal movements are largely unaffected. The gene was tagged for molecular cloning by two independent transposon insertions. Based on genomic and cDNA sequencing, the gene encodes a novel laminin-related protein, UNC-6 (591 amino acids). The N-terminus is homologous to the N-termini (i.e., domains VI, V-1, V-2, and V-3) of laminin subunits, while the C-terminus is a unique domain. We propose that UNC-6 is a component of an extracellular matrix cue that guides dorsoventral migrations on the epidermis.

The polarization of post-mitotic neurons is poorly understood. Preexisting spatially asymmetric c... more The polarization of post-mitotic neurons is poorly understood. Preexisting spatially asymmetric cues, distributed within the neuron or as extracellular gradients, could be required for neurons to polarize. Alternatively, neurons might have the intrinsic ability to polarize without any preestablished asymmetric cues. In Caenorhabditis elegans, the UNC-40 (DCC) receptor mediates responses to the extracellular UNC-6 (netrin) guidance cue. For the HSN neuron, an UNC-6 ventral-dorsal gradient asymmetrically localizes UNC-40 to the ventral HSN surface. There an axon forms, which is ventrally directed by UNC-6. In the absence of UNC-6, UNC-40 is equally distributed and the HSN axon travels anteriorly in response to other cues. However, we find that a single amino acid change in the UNC-40 ectodomain causes randomly oriented asymmetric UNC-40 localization and a wandering axon phenotype. With UNC-6, there is normal UNC-40 localization and axon migration. A single UNC-6 amino acid substitution enhances the mutant phenotypes, whereas UNC-6 second-site amino acid substitutions suppress the phenotypes. We propose that UNC-40 mediates multiple signals to polarize and orient asymmetry. One signal triggers the intrinsic ability of HSN to polarize and causes randomly oriented asymmetry. Concurrently, another signal biases the orientation of the asymmetry relative to the UNC-6 gradient. The UNC-40 ectodomain mutation activates the polarization signal, whereas different forms of the UNC-6 ligand produce UNC-40 conformational changes that allow or prohibit the orientation signal.

How extracellular molecules influence the direction of axon guidance is poorly understood. The HS... more How extracellular molecules influence the direction of axon guidance is poorly understood. The HSN axon of Caenorhabditis
elegans is guided towards a ventral source of secreted UNC-6 (netrin). The axon’s outgrowth response to UNC-6 is mediated
by the UNC-40 (DCC) receptor. We have proposed that in response to the UNC-6 molecule the direction of UNC-40-
mediated axon outgrowth is stochastically determined. The direction of guidance is controlled by asymmetric cues,
including the gradient of UNC-6, that regulate the probability that UNC-40-mediated axon outgrowth is directed on
average, over time, in a specific direction. Here we provide genetic evidence that a specialized extracellular matrix, which
lies ventral to the HSN cell body, regulates the probability that UNC-40-mediated axon outgrowth will be directed ventrally
towards the matrix. We show that mutations that disrupt the function of proteins associated with this matrix, UNC-52
(perlecan), UNC-112 (kindlin), VAB-19 (Kank), and UNC-97 (PINCH), decrease the probability of UNC-40-mediated axon
outgrowth in the ventral direction, while increasing the probability of outgrowth in the anterior and posterior directions.
Other results suggest that INA-1 (a integrin) and MIG-15 (NIK kinase) signaling mediate the response in HSN. Although the
AVM axon also migrates through this matrix, the mutations have little effect on the direction of AVM axon outgrowth,
indicating that responses to the matrix are cell-specific. Together, these results suggest that an extracellular matrix can
regulate the direction of UNC-6 guidance by increasing the probability that UNC-40-mediated axon outgrowth activity will
be oriented in a specific direction.

How the direction of axon guidance is determined is not understood. In Caenorhabditis elegans th... more How the direction of axon guidance is determined is not
understood. In Caenorhabditis elegans the UNC-40 (DCC)
receptor mediates a response to the UNC-6 (netrin) guidance
cue that directs HSN axon development. UNC-40 becomes
asymmetrically localized within the HSN neuron to the site of
axon outgrowth. Here we provide experimental evidence that
the direction of guidance can be explained by the stochastic
fluctuations of UNC-40 asymmetric outgrowth activity. We
find that the UNC-5 (UNC5) receptor and the cytoskeletal
binding protein UNC-53 (NAV2) regulate the induction of
UNC-40 localization by UNC-6. If UNC-40 localization is
induced without UNC-6 by using an unc-53 mutation, the
direction of UNC-40 localization undergoes random
fluctuations. Random walk models describe the path made by
a succession of randomly directed movement. This model was
experimentally tested using mutations that affect Wnt/PCP
signaling. These mutations inhibit UNC-40 localization in the
anterior and posterior directions. As the axon forms in Wnt/
PCP mutants, the direction of UNC-40 localization randomly
fluctuates; it can localize in either the anterior, posterior, or
ventral direction. Consistent with a biased random walk, over
time the axon will develop ventrally in response to UNC-6, even
though at a discrete time UNC-40 localization and outgrowth
can be observed anterior or posterior. Also, axon formation is
slower in the mutants than in wild-type animals. This is also
consistent with a random walk since this model predicts that
the mean square displacement (msd) will increase only linearly
with time, whereas the msd increases quadratically with time
for straight-line motion.

Axons in Caenorhabditis elegans are guided by multiple extracellular cues, including UNC-6 (netri... more Axons in Caenorhabditis elegans are guided by multiple extracellular cues, including UNC-6 (netrin), EGL-20 (wnt), UNC-52
(perlecan), and SLT-1 (slit). How multiple extracellular cues determine the direction of axon guidance is not well understood.
We have proposed that an axon’s response to guidance cues can be modeled as a random walk, i.e., a succession of
randomly directed movement. Guidance cues dictate the probability of axon outgrowth activity occurring in each direction,
which over time creates a directional bias. Here we provide further evidence for this model. We describe the effects that the
UNC-40 (DCC) and SAX-3 (Robo) receptors and the UNC-6, EGL-20, UNC-52, and SLT-1 extracellular cues have on the
directional bias of the axon outgrowth activity for the HSN and AVM neurons. We find that the directional bias created by
the cues depend on UNC-40 or SAX-3. UNC-6 and EGL-20 affect the directional bias for both neurons, whereas UNC-52 and
SLT-1 only affect the directional bias for HSN and AVM, respectively. The direction of the bias created by the loss of a cue
can vary and the direction depends on the other cues. The random walk model predicts this combinatorial regulation. In a
random walk a probability is assigned for each direction of outgrowth, thus creating a probability distribution. The
probability distribution for each neuron is determined by the collective effect of all the cues. Since the sum of the
probabilities must equal one, each cue affects the probability of outgrowth in multiple directions.

Journal of Neuroscience, 2008

In the developing nervous system, axons respond to various guidance cues to find their targets. T... more In the developing nervous system, axons respond to various guidance cues to find their targets. The effects guidance cues have on an axon may change as an axon undergoes morphological changes, such as branching, turning, and synapse formation. The means by which these changes are regulated are not well understood. In C. elegans, the UNC-40/DCC receptor mediates responses to the UNC-6/netrin guidance cue. Here we show that CLEC-38, a protein with predicted transmembrane and C-type lectin-like domains, regulates UNC-40-mediated axon outgrowth as well as the organization of presynaptic terminals. We observe that in genetic backgrounds sensitized for axon guidance defects, loss of clec-38 function can suppress defects in an UNC-40-dependant manner. Within migrating axons, clec-38 acts cell-autonomously. Further, loss of clec-38 function alters UNC-40::GFP expression. We also observe that loss of clec-38 function disrupts presynaptic patterning in animals with normal axon guidance and that there are genetic interactions between clec-38 and rpm-1, which encodes a protein implicated in regulating presynaptic assembly and axon morphology. We suggest CLEC-38 plays a role in promoting synapse assembly and refining axon outgrowth activity.

Journal of Lipid Research, 2003

J Lipid Res, 2003

Current Opinion in Neurobiology, 1992

Genetics, 2011

The Journal of Lipid Research, 2003

Developmental Biology, 2006

Neuron, 1996

Journal of Neurobiology, 1999

Current Biology, 2008

Current Biology, 2006

UNC-6, a laminin-related protein, guides cell and pioneer axon migrations in C. elegans, Nov 1992

How extracellular molecules influence the direction of axon guidance is poorly understood. The HS... more How extracellular molecules influence the direction of axon guidance is poorly understood. The HSN axon of Caenorhabditis
elegans is guided towards a ventral source of secreted UNC-6 (netrin). The axon’s outgrowth response to UNC-6 is mediated
by the UNC-40 (DCC) receptor. We have proposed that in response to the UNC-6 molecule the direction of UNC-40-
mediated axon outgrowth is stochastically determined. The direction of guidance is controlled by asymmetric cues,
including the gradient of UNC-6, that regulate the probability that UNC-40-mediated axon outgrowth is directed on
average, over time, in a specific direction. Here we provide genetic evidence that a specialized extracellular matrix, which
lies ventral to the HSN cell body, regulates the probability that UNC-40-mediated axon outgrowth will be directed ventrally
towards the matrix. We show that mutations that disrupt the function of proteins associated with this matrix, UNC-52
(perlecan), UNC-112 (kindlin), VAB-19 (Kank), and UNC-97 (PINCH), decrease the probability of UNC-40-mediated axon
outgrowth in the ventral direction, while increasing the probability of outgrowth in the anterior and posterior directions.
Other results suggest that INA-1 (a integrin) and MIG-15 (NIK kinase) signaling mediate the response in HSN. Although the
AVM axon also migrates through this matrix, the mutations have little effect on the direction of AVM axon outgrowth,
indicating that responses to the matrix are cell-specific. Together, these results suggest that an extracellular matrix can
regulate the direction of UNC-6 guidance by increasing the probability that UNC-40-mediated axon outgrowth activity will
be oriented in a specific direction.

Journal of Neuroscience, 2008

Journal of Lipid Research, 2003

J Lipid Res, 2003

Understanding axon guidance is important for developing therapies to restore neuronal connections... more Understanding axon guidance is important for developing therapies to restore neuronal connections damaged by injury or disease. Axons migrate in response to extracellular guidance molecules that induce or inhibit axon outgrowth activity within the axon. The direction of guidance is determined by the attractive and repulsive responses that the axon has to the guidance cues. In a deterministic model of guidance, the direction of guidance can be precisely determined if the attractive and repulsive effect that each cue has on the axon is known. But what if there are numerous attractive and repulsive responses induced by multiple guidance cues, and the direction of the attractive and repulsive events fluctuates? If the effect that each attractive and repulsive event has on guidance becomes too complex to measure then understanding how each molecular cue influences the guidance decision becomes impossible. In a series of papers, we have argued that it is useful to study axon guidance as a stochastic process. This approach treats all the outgrowth activities in aggregate. Attraction and repulsion are considered as unpredictable events that occur at the molecular level. The contribution to guidance of each attractive or repulsive event becomes insignificant. Using this probabilistic approach, guidance is considered as macroscopic movement that is the product of the collective impact of all the underlying axon outgrowth events. Directionality is the product of a succession of randomly directed
movement. This movement can be studied using the methods of statistical physics. In this perceptive article, I explain the rationale behind this theory and its significance for understanding axon guidance.

Bioessays, 1996

During embryogenesis, the basic axon scaffold of the nervous system is formed by special axons th... more During embryogenesis, the basic axon scaffold of the nervous system is formed by special axons that pioneer pathways between groups of cells. To find their way, the pioneer growth cones detect specific cues in their extracellular environment. One of these guidance cues is netrin. Observations and experimental manipulations in vertebrates and nematodes have shown that netrin is a bifunctional guidance cue that can simultaneously attract and repel axons. During the formation of this basic axon scaffold in Caenorhabditis elegans, the netrin UNC-6 is expressed by neuroglia and pioneer neurons, providing hierarchical guidance cues throughout the animal. Each cue has a characteristic role depending on the cell type, its position and the developmental stage. These roles include activities as global, decussation and labeled-pathway cues. This hierarchical model of UNC-6 netrin-mediated guidance suggests a method by which guidance cues can direct formation of basic axon scaffolds in developing nervous systems.

Trends in Neurosciences, 2002

Current Opinion in Cell Biology, 2004

Vertebrate laminins and netrins share N-terminal domain structure, but appear to be only distantl... more Vertebrate laminins and netrins share N-terminal domain structure, but appear to be only distantly related. Both families can be divided into different subfamilies on the basis of structural considerations. Recent observations suggest that specific laminin and netrin members have developmental functions that are highly conserved across species. Vertebrate laminin-1 (a1b1g1) and laminin-10 (a5b1g1), like the two Caenorhabditis elegans laminins, are embryonically expressed and are essential for basement membrane assembly. Basement membrane assembly is a cooperative process in which laminins polymerize through their LN domains and anchor to the cell surface through their G domains; this leads to cell signaling through integrins and dystroglycan (and possibly other receptors) recruited to the adherent laminin. Netrins may associate with this network through heterotypic LN domain interactions. Vertebrate netrin-1, like invertebrate UNC-6/ netrins, is well known as an extracellular guidance cue that directs axon migration towards or away from the ventral midline. It also regulates cell adhesions and migrations, probably as a basement membrane component. Although sharing structural features, these two vertebrate protein families are quite distinct, having both retained members that mediate the ancestral developmental functions.

Current Biology, 2005

equally matched by their spectacular diversity in morphology and body colouration [10]. As well a... more equally matched by their spectacular diversity in morphology and body colouration [10]. As well as expanding into unoccupied ecological niches, sexual selection of body colour variation among males, by female cichlids, is thought to contribute to the incredibly fast rates of speciation [10]. Sexual selection may be an even more important factor in driving rapid speciation in the clear-water environment of Lake Malawi. It would be very interesting to compare the spectral composition of body colour patterns with the maximal spectral sensitivities of the expressed cone opsins in the Lake Malawi cichlids. Selection pressure to match, or tune, the visual sensitivities of the opsins to the local light environment may also contribute to speciation.

Current Biology, 2006

Recent findings indicate that the embryonic motor neurons act as gatekeepers to regulate midline ... more Recent findings indicate that the embryonic motor neurons act as gatekeepers to regulate midline crossing during development of the nematode Caenorhabditis elegans. The newly identified protein WRK-1 and ephrins cooperate to prevent longitudinal axons from crossing the midline.

Nature Biotechnology, 2002

Trends in Cell Biology, 2008

A network of connections is established as neural circuits form between neurons. To make these co... more A network of connections is established as neural circuits form between neurons. To make these connections, neurons initiate asymmetric axon outgrowth in response to extracellular guidance cues. Within the specialized growth cones of migrating axons, F-actin and microtubules asymmetrically accumulate where an axon projects forward. Although many guidance cues, receptors, and intracellular signaling components required for axon guidance have been identified, the means through which the asymmetry is established and maintained is unclear. We discuss recent studies in invertebrate and vertebrate organisms that define a signaling module comprising UNC-6(netrin), UNC-40(DCC), PI3K, Rac, and MIG-10(lamellipodin) and we consider how this module could establish polarized outgrowth in response to guidance cues.

Over a four-month period in 1905, Einstein published a series of remarkable papers that changed o... more Over a four-month period in 1905, Einstein published a series of remarkable papers that changed our conception of time and space. Even more remarkable is the instrument that enabled Einstein to unlock the mysteries of time and space. His brain.

The man claimed he was a wizard and had cast the “spell of attraction” on the target. Now the ta... more The man claimed he was a wizard and had cast the “spell of attraction” on the target. Now the target would guide his arrow to the mark. So we gave the man a broken arrow and watched to see if this arrow could hit the target. The man took the arrow and flung it at the target. Indeed, this arrow too could hit the target.

An axon is attracted towards its target by guidance cues. A moth flies towards the source of a p... more An axon is attracted towards its target by guidance cues. A moth flies towards the source of a pheromone. A spider is sucked across the floor towards the nozzle of a vacuum cleaner. Is the attraction of an axon towards its target more like the movement of the moth or the spider?

The proposition that the response of an axon to guidance cues is a random walk provides a differe... more The proposition that the response of an axon to guidance cues is a random walk provides a different perspective of axon guidance.
For the most part, Biologists like deterministic models, i.e. cause and effect. From the deterministic point-of-view, axon guidance is caused when axon outgrowth activity occurs at the site where the neuron detects an external attractive guidance cue.
But what if the direction of axon outgrowth activity were to rapidly fluctuate in different directions?

Attractants and repellants guide axons to their targets. On its journey, a migrating axon may be... more Attractants and repellants guide axons to their targets. On its journey, a migrating axon may be confronted with multiple attractive and repulsive guidance cues. This presents a conundrum. How does the axon avoid a tug-of-war between attractants and repellants? Does the strongest cue win? Can one cue negate the effects of another? Can an axon switch its responsiveness to cues until they all match?

Our study suggests that the key to understanding this problem may lie within the realm of probability theory.

The polarization of post-mitotic neurons is poorly understood. Pre-existing spatially asymmetric ... more The polarization of post-mitotic neurons is poorly understood. Pre-existing spatially asymmetric cues, distributed within the neuron or as extracellular gradients, could be required for neurons to polarize. Alternatively, neurons might have the intrinsic ability to polarize without any pre-established asymmetric cues. In C. elegans, the UNC-40 (DCC) receptor mediates responses to the extracellular UNC-6 (netrin) guidance cue. For the HSN neuron, an UNC-6 ventral-dorsal gradient asymmetrically localizes UNC-40 to the ventral HSN surface.