Ev Nichols

All Publications

• All In: Understanding and Motivating Stakeholders to Create an Equitable Culture of Student Success. CBE life sciences education Weatherton, M., Ko, M. E., Nichols, E. L., Krishnan, S., Faber, C. 2024; 23 (4): es10

  Abstract

  Discourse around Science, Technology, Engineering, and Mathematics (STEM) education in the United States has long focused on improving the persistence and academic achievement of students. On the surface, such goals are reasonable and well-intentioned. However, the near-exclusive focus on those two outcomes as shorthand for "success" serves hegemonic norms which preclude the equitable success of all students. Although STEM education research has begun to address the inequitable systems within which students and faculty operate, the language of success has largely not changed. While previous work has aimed to recognize and characterize how normative definitions of success harm students and faculty, they fall short of providing readers with strategies for how to sustainably change these systems of injustice. Utilizing the four frames model for systemic change, this Essay 1) deconstructs the operational definitions of student success among key stakeholders involved in STEM higher education: students, faculty, departments, and institutions; 2) determines how extant policies and practices drive misalignments among these definitions and thwart equity; and 3) highlights three key opportunities for change agents to transform how success is measured and defined within STEM higher education.

  View details for DOI 10.1187/cbe.24-02-0065

  View details for PubMedID 39418170

• A debate in bad faith: naming anti-transgender bias in The Journal of Physiology. The Journal of physiology Nichols, E. L. 2024

  View details for DOI 10.1113/JP287492

  View details for PubMedID 39256994

• Structural insights into the formation of repulsive netrin guidance complexes. Science advances Priest, J. M., Nichols, E. L., Smock, R. G., Hopkins, J. B., Mendoza, J. L., Meijers, R., Shen, K., Özkan, E. 2024; 10 (7): eadj8083

  Abstract

  Netrins dictate attractive and repulsive responses during axon growth and cell migration, where the presence of the receptor Uncoordinated-5 (UNC-5) on target cells results in repulsion. Here, we showed that UNC-5 is a heparin-binding protein, determined its structure bound to a heparin fragment, and could modulate UNC-5-heparin affinity using a directed evolution platform or structure-based rational design. We demonstrated that UNC-5 and UNC-6/netrin form a large, stable, and rigid complex in the presence of heparin, and heparin and UNC-5 exclude the attractive UNC-40/DCC receptor from binding to UNC-6/netrin to a large extent. Caenorhabditis elegans with a heparin-binding-deficient UNC-5 fail to establish proper gonad morphology due to abrogated cell migration, which relies on repulsive UNC-5 signaling in response to UNC-6. Combining UNC-5 mutations targeting heparin and UNC-6/netrin contacts results in complete cell migration and axon guidance defects. Our findings establish repulsive netrin responses to be mediated through a glycosaminoglycan-regulated macromolecular complex.

  View details for DOI 10.1126/sciadv.adj8083

  View details for PubMedID 38363837

• A Subset of Oligodendrocyte Lineage Cells Interact With the Developing Dorsal Root Entry Zone During Its Genesis FRONTIERS IN CELLULAR NEUROSCIENCE Green, L. A., Gallant, R. M., Brandt, J. P., Nichols, E. L., Smith, C. J. 2022; 16: 893629

  Abstract

  Oligodendrocytes are the myelinating cell of the CNS and are critical for the functionality of the nervous system. In the packed CNS, we know distinct profiles of oligodendrocytes are present. Here, we used intravital imaging in zebrafish to identify a distinct oligodendrocyte lineage cell (OLC) that resides on the dorsal root ganglia sensory neurons in the spinal cord. Our profiling of OLC cellular dynamics revealed a distinct cell cluster that interacts with peripheral sensory neurons at the dorsal root entry zone (DREZ). With pharmacological, physical and genetic manipulations, we show that the entry of dorsal root ganglia pioneer axons across the DREZ is important to produce sensory located oligodendrocyte lineage cells. These oligodendrocyte lineage cells on peripherally derived sensory neurons display distinct processes that are stable and do not express mbpa. Upon their removal, sensory behavior related to the DRG neurons is abolished. Together, these data support the hypothesis that peripheral neurons at the DREZ can also impact oligodendrocyte development.

  View details for DOI 10.3389/fncel.2022.893629

  View details for Web of Science ID 000813397200001

  View details for PubMedID 35734217

  View details for PubMedCentralID PMC9207214

• Pioneer Axons Utilize a Dcc Signaling-Mediated Invasion Brake to Precisely Complete Their Pathfinding Odyssey JOURNAL OF NEUROSCIENCE Kikel-Coury, N. L., Green, L. A., Nichols, E. L., Zellmer, A. M., Pai, S., Hedlund, S. A., Marsden, K. C., Smith, C. J. 2021; 41 (31): 6617-6636

  Abstract

  Axons navigate through the embryo to construct a functional nervous system. A missing part of the axon navigation puzzle is how a single axon traverses distinct anatomic choice points through its navigation. The dorsal root ganglia (DRG) neurons experience such choice points. First, they navigate to the dorsal root entry zone (DREZ), then halt navigation in the peripheral nervous system to invade the spinal cord, and then reinitiate navigation inside the CNS. Here, we used time-lapse super-resolution imaging in zebrafish DRG pioneer neurons to investigate how embryonic axons control their cytoskeleton to navigate to and invade at the correct anatomic position. We found that invadopodia components form in the growth cone even during filopodia-based navigation, but only stabilize when the axon is at the spinal cord entry location. Further, we show that intermediate levels of DCC and cAMP, as well as Rac1 activation, subsequently engage an axon invasion brake. Our results indicate that actin-based invadopodia components form in the growth cone and disruption of the invasion brake causes axon entry defects and results in failed behavioral responses, thereby demonstrating the importance of regulating distinct actin populations during navigational challenges.SIGNIFICANCE STATEMENT Correct spatiotemporal navigation of neuronal growth cones is dependent on extracellular navigational cues and growth cone dynamics. Here, we link dcc-mediated signaling to actin-based invadopodia and filopodia dynamics during pathfinding and entry into the spinal cord using an in vivo model of dorsal root ganglia (DRG) sensory axons. We reveal a molecularly-controlled brake on invadopodia stabilization until the sensory neuron growth cone is present at the dorsal root entry zone (DREZ), which is ultimately essential for growth cone entry into the spinal cord and behavioral response.

  View details for DOI 10.1523/JNEUROSCI.0212-21.2021

  View details for Web of Science ID 000684594500005

  View details for PubMedID 34131031

  View details for PubMedCentralID PMC8336704

• Functional Regeneration of the Sensory Root via Axonal Invasion CELL REPORTS Nichols, E. L., Smith, C. J. 2020; 30 (1): 9-+

  Abstract

  Regeneration following spinal root avulsion is broadly unsuccessful despite the regenerative capacity of other PNS-located nerves. By combining focal laser lesioning to model root avulsion in zebrafish, time-lapse imaging, and transgenesis, we identify that regenerating DRG neurons fail to recapitulate developmental paradigms of actin-based invasion after injury. We demonstrate that inducing actin reorganization into invasive components via pharmacological and genetic approaches in the regenerating axon can rescue sensory axon spinal cord entry. Cell-autonomous induction of invasion components using constitutively active Src induces DRG axon regeneration, suggesting an intrinsic mechanism can be activated to drive regeneration. Furthermore, analyses of neuronal activity and animal behavior show restoration of sensory circuit activity and behavior upon stimulating axons to re-enter the spinal cord via invasion. Altogether, our data identify induction of invasive components as sufficient for functional sensory root regeneration after injury.

  View details for DOI 10.1016/j.celrep.2019.12.008

  View details for Web of Science ID 000506009500002

  View details for PubMedID 31914401

  View details for PubMedCentralID PMC6996490

• Synaptic-like Vesicles Facilitate Pioneer Axon Invasion. Current biology : CB Nichols, E. L., Smith, C. J. 2019

  Abstract

  Synaptic vesicles are indispensable for neuronal communication in mature circuits. Synaptic vesicle biogenesis must be concurrent with axon navigation for synaptogenesis, but whether synaptic vesicles are functionally employed in circuit formation before synaptogenesis is poorly understood. Here, we use time-lapse imaging and transgenesis in zebrafish to visualize the role of synaptic-like vesicles in navigation of dorsal root ganglia pioneer axons. We identify that synaptic-like vesicles accumulate in the central growth cone as the pioneer axon breaches the spinal boundary at the dorsal root entry zone. Inhibition of vesicle release with cell-specific tetanus toxin expression results in pioneer axon pathfinding defects and altered spinal entry. We further show that the matrix metalloproteinase (MMP) mmp14a is required in pioneer axons to navigate across the boundary of the spinal cord and, with super-resolution microscopy, is positioned with synaptic vesicles at the boundary. Manipulations of concurrent actin reorganization reveal that actin remodeling drives vesicle release and subsequent MMP activity. Together, these data point to an indispensable role for synaptic-like vesicles at specific points in axon navigation as regulators of growth cone microenvironment.

  View details for DOI 10.1016/j.cub.2019.06.078

  View details for PubMedID 31378609

• Generating intravital super-resolution movies with conventional microscopy reveals actin dynamics that construct pioneer axons DEVELOPMENT Zhang, Y., Nichols, E. L., Zellmer, A. M., Guldner, I. H., Kankel, C., Zhang, S., Howard, S. S., Smith, C. J. 2019; 146 (5)

  Abstract

  Super-resolution microscopy is broadening our in-depth understanding of cellular structure. However, super-resolution approaches are limited, for numerous reasons, from utilization in longer-term intravital imaging. We devised a combinatorial imaging technique that combines deconvolution with stepwise optical saturation microscopy (DeSOS) to circumvent this issue and image cells in their native physiological environment. Other than a traditional confocal or two-photon microscope, this approach requires no additional hardware. Here, we provide an open-access application to obtain DeSOS images from conventional microscope images obtained at low excitation powers. We show that DeSOS can be used in time-lapse imaging to generate super-resolution movies in zebrafish. DeSOS was also validated in live mice. These movies uncover that actin structures dynamically remodel to produce a single pioneer axon in a 'top-down' scaffolding event. Further, we identify an F-actin population - stable base clusters - that orchestrate that scaffolding event. We then identify that activation of Rac1 in pioneer axons destabilizes stable base clusters and disrupts pioneer axon formation. The ease of acquisition and processing with this approach provides a universal technique for biologists to answer questions in living animals.

  View details for DOI 10.1242/dev.171512

  View details for Web of Science ID 000461331900006

  View details for PubMedID 30760484

  View details for PubMedCentralID PMC6432666

• Pioneer axons employ Cajal's battering ram to enter the spinal cord NATURE COMMUNICATIONS Nichols, E. L., Smith, C. J. 2019; 10: 562

  Abstract

  Sensory axons must traverse a spinal cord glia limitans to connect the brain with the periphery. The fundamental mechanism of how these axons enter the spinal cord is still debatable; both Ramon y Cajal's battering ram hypothesis and a boundary cap model have been proposed. To distinguish between these hypotheses, we visualized the entry of pioneer axons into the dorsal root entry zone (DREZ) with time-lapse imaging in zebrafish. Here, we identify that DRG pioneer axons enter the DREZ before the arrival of neural crest cells at the DREZ. Instead, actin-rich invadopodia in the pioneer axon are necessary and sufficient for DREZ entry. Using photoactivable Rac1, we demonstrate cell-autonomous functioning of invasive structures in pioneer axon spinal entry. Together these data support the model that actin-rich invasion structures dynamically drive pioneer axon entry into the spinal cord, indicating that distinct pioneer and secondary events occur at the DREZ.

  View details for DOI 10.1038/s41467-019-08421-9

  View details for Web of Science ID 000457582900006

  View details for PubMedID 30718484

  View details for PubMedCentralID PMC6362287

• Ensheathing cells utilize dynamic tiling of neuronal somas in development and injury as early as neuronal differentiation NEURAL DEVELOPMENT Nichols, E. L., Green, L. A., Smith, C. J. 2018; 13: 19

  Abstract

  Glial cell ensheathment of specific components of neuronal circuits is essential for nervous system function. Although ensheathment of axonal segments of differentiated neurons has been investigated, ensheathment of neuronal cell somas, especially during early development when neurons are extending processes and progenitor populations are expanding, is still largely unknown.To address this, we used time-lapse imaging in zebrafish during the initial formation of the dorsal root ganglia (DRG).Our results show that DRG neurons are ensheathed throughout their entire lifespan by a progenitor population. These ensheathing cells dynamically remodel during development to ensure axons can extend away from the neuronal cell soma into the CNS and out to the skin. As a population, ensheathing cells tile each DRG neuron to ensure neurons are tightly encased. In development and in experimental cell ablation paradigms, the oval shape of DRG neurons dynamically changes during partial unensheathment. During longer extended unensheathment neuronal soma shifting is observed. We further show the intimate relationship of these ensheathing cells with the neurons leads to immediate and choreographed responses to distal axonal damage to the neuron.We propose that the ensheathing cells dynamically contribute to the shape and position of neurons in the DRG by their remodeling activity during development and are primed to dynamically respond to injury of the neuron.

  View details for DOI 10.1186/s13064-018-0115-8

  View details for Web of Science ID 000441983300001

  View details for PubMedID 30121077

  View details for PubMedCentralID PMC6098834