From Hammarlund Lab
Welcome to the Hammarlund Lab
Toward an immortal brain
Individual neurons sometimes continue working for the life of the animal. In other cases, their function is abrogated by injury, disease, or age-associated decline. Since damaged or dead neurons generally cannot be replaced, the continuing function of our nervous system depends on the ability of our individual neurons to survive for as long as we do: repairing damage, resisting disease, and maintaining function over the long term. Neurons are complex cells with an extended and fragile morphology. Each neuron must generate and maintain delicate balances in membrane potential, trafficking, and secretion to perform its function. How do neurons sometimes survive and continue to function for decades, and why do they sometimes fail?
We study the cell-biological mechanisms that modulate neuronal endurance. We use the model organism C. elegans, which allows us to analyze neuronal structure and function in adult animals, in vivo, with single-neuron resolution—an approach that is difficult in other systems. We develop novel molecular and genetic tools, which we use together with single-neuron laser axotomy, in vivo imaging, optogenetics, electron microscopy, and genetic analysis, to address two fundamental questions:
- 1) How do neurons maintain their structure and their ability to transmit information?
- 2) How do neurons repair themselves when they are damaged?
Answering these questions will provide fundamental insights into the mechanisms that attempt to maintain neuronal cellular and circuit function over time: when successful, allowing the brain to outlast the body; when unsuccessful, increasing susceptibility to cognitive decline and neurological disease. By understanding and manipulating these mechanisms we aim to prevent the decline of the nervous system, resulting in its immortality.
Our paper, "Neural Regeneration in Caenorhabditis elegans", published in Annual Review of Genetics
- Summary: Axon regeneration is a medically relevant process that can repair damaged neurons. This review describes current progress in understanding axon regeneration in the model organism Caenorhabditis elegans. Factors that regulate axon regeneration in C. elegans have broadly similar roles in vertebrate neurons. This means that using C. elegans as a tool to leverage discovery is a legitimate strategy for identifying conserved mechanisms of axon regeneration.
End of the 2012 Hammarlund Lab Summer Undergrad Program. Thanks to Will, Chukwuma, Kevin, and (amazing high school student) Austin!
Article about our Notch research published in Scientific American
Our meeting review, "Science in Suzhou: establishment and function of neural circuits", published in EMBO Reports! PDF
- Summary: The CSH Asia conference ‘Assembly, Plasticity, Dysfunction and Repair of Neural Circuits’ brought together developmental, cell, molecular and systems neuroscientists to discuss the establishment, function and plasticity of neural circuits.
Our paper, "Notch Signaling Inhibits Axon Regeneration", published in Neuron! PDF
- Summary: Many neurons have limited capacity to regenerate their axons after injury. Neurons in the mammalian central nervous system do not regenerate, and even neurons in the peripheral nervous system often fail to regenerate to their former targets. This failure is likely due in part to pathways that actively restrict regeneration; however, only a few factors that limit regeneration are known. Here, using single-neuron analysis of regeneration in vivo, we show that Notch/lin-12 signaling inhibits the regeneration of mature C. elegans neurons. Notch signaling suppresses regeneration by acting autonomously in the injured cell to prevent growth cone formation. The metalloprotease and gamma-secretase cleavage events that lead to Notch activation during development are also required for its activity in regeneration. Furthermore, blocking Notch activation immediately after injury improves regeneration. Our results define a postdevelopmental role for the Notch pathway as a repressor of axon regeneration in vivo.
Neuron Preview by Po, Calarco, and Zhen: PDF
Yale undergrad Trent Walradt joins the lab. Welcome Trent!
Happy Holidays from the Hammarlund lab! (Cookies by Rebecca Brown from the CNNR Bakeoff)
End of the 2011 Hammarlund Lab Summer Undergrad Program. Thanks to Jaimie, Quinn, Reba, and Yigit!
Sara passes her qualifying exams. Congratulations!
- Summary: Neurons communicate with other cells via axons and dendrites, slender membrane extensions that contain pre- or post-synaptic specializations. If a neuron is damaged by injury or disease, it may regenerate. Cell-intrinsic and extrinsic factors influence the ability of a neuron to regenerate and restore function. Recently, the nematode C. elegans has emerged as an excellent model organism to identify genes and signaling pathways that influence the regeneration of neurons. The main way to initiate neuronal regeneration in C. elegans is laser-mediated cutting, or axotomy. During axotomy, a fluorescently-labeled neuronal process is severed using high-energy pulses. Initially, neuronal regeneration in C. elegans was examined using an amplified femtosecond laser. However, subsequent regeneration studies have shown that a conventional pulsed laser can be used to accurately sever neurons in vivo and elicit a similar regenerative response.
- We present a protocol for performing in vivo laser axotomy in the worm using a MicroPoint® pulsed laser, a turnkey system that is readily available and that has been widely used for targeted cell ablation. We describe aligning the laser, mounting the worms, cutting specific neurons, and assessing subsequent regeneration. The system provides the ability to cut large numbers of neurons in multiple worms during one experiment. Thus, laser axotomy as described herein is an efficient system for initiating and analyzing the process of regeneration.
Goodbye to new Yale Graduate and amazing lab member Ellie Hong!
December 9: Some of Marc's work from his first postdoc (Syntaxin N-terminal peptide motif is an initiation factor for the assembly of the SNARE–Sec1/Munc18 membrane fusion complex) published in PNAS
November 11: Chris passes his qualifying exam. Congratulations Chris!
November 5: Genetics Department Annual Retreat at Jiminy Peak. Faculty photo
October 19: Some of Chris' work from college (Modifiers of notch transcriptional activity identified by genome-wide RNAi) published in BMC Developmental Biology
August 12: Welcome postdoc Yasunori Saheki!
August 9: With a small tear in his eye, Dan heads west for a Visiting Assistant Professor position at Linfield College. Good Luck Dan!!
June 27-30: Neuronal Development, Synaptic Function, and Behavior C. elegans Topic Meeting.
June 15: Some of Alex's work from grad school (MADD-2, a Homolog of the Opitz Syndrome Protein MID1, Regulates Guidance to the Midline through UNC-40 in Caenorhabditis elegans) published in Developmental Cell
June 14: Welcome grad student Sara Kosmaczewski!
May 24: Welcome undergraduate Ellie Hong!
April 27: Tyson passes his qualifying exam. Congratulations Tyson!
October 6: Welcome postdoc Alexandra Byrne!
June 24-28: International C. elegans Meeting
June 10: "Imaging Axon Regeneration in vivo", Yale Microscopy Workshop
May 18: Welcome grad student Tyson Edwards!
May 7: Welcome grad student Christopher Firnhaber!
April 24: Arnold and Mabel Beckman Foundation Young Investigator Award.
Jan. 22: "Axon regeneration requires a conserved MAP kinase pathway" published in Science. PDF
Jan. 12: Welcome technician Laura Klein!
Dec. 12: Genetics Department Holiday Party
Dec. 11: CNNR Open House
The fact is the sweetest dream that labor knows. --Robert Frost