Tag Archives: Department of Cell and Developmental Biology

Vanderbilt staff works throughout disciplines to copy

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A Vanderbilt College laboratory led by Marija Zanic, assistant professor of cell and developmental biology, has demonstrated for the primary time how microtubules—filaments which can be important to a lot of a cell’s capabilities—transfer round in a course of often called treadmilling.

Marija Zanic (Anne Rayner, Vanderbilt College)

“With out an interdisciplinary method and the power to simulate the experiment, the analysis would have been a futile try.” 

Microtubules are vital in capabilities starting from cell division to a cell’s means to retain its form. Understanding the method of how these filaments use vitality to inch across the cell inside, rising at one finish and shrinking on the different, might unlock insights into potential illness therapies.

An article in regards to the analysis, “Collective results of XMAP215, EB1, CLASP2, and MCAK result in sturdy microtubule treadmilling,” was revealed on-line within the journal Proceedings of the Nationwide Academy of Sciences on June 9.

Utilizing high-end microscopy, Zanic and her staff studied microtubules outdoors of cells and away from the proteins that affect their habits. From this vantage level the group noticed the important dynamics of treadmilling and experimented by including quite a lot of proteins and reagents to the microtubules to see what would change.

The lab was in a position to observe the consequences of quite a few totally different “protein recipes” with a pc simulation approach, fairly than take a look at mixtures in an infinite collection of experiments. With pc modeling, the staff discovered that combining tubulin and 4 different proteins encourages the identical form of treadmilling that happens naturally inside cells. That is the primary time that any analysis group has been in a position to replicate this habits outdoors of cells and carries probably widespread alternatives for future analysis.“With none further proteins, microtubules by themselves moved slowly and in the other way of what we see in cells,” mentioned Goker Arpag, the paper’s co-first writer and a postdoctoral analysis fellow within the Zanic lab. It was solely after researchers added protein parts that they might replicate treadmilling habits.

Goker Arpag (Vanderbilt College)
Beth Lawrence (Beth Lawrence)

By figuring out the particular proteins that modulate a cell’s perform, scientists could possibly develop therapies for illnesses and well being situations linked to microtubule habits. “If we will get these polymers to do what we would like—on this case to change the method of treadmilling—we now have the power to manage cell habits,” mentioned Zanic, additionally assistant professor of chemical and biomolecular engineering and biochemistry.

As a result of microtubules are answerable for cell division and are targets for chemotherapy, this analysis is broadly relevant to cancer-related analysis. This analysis additionally has relevance for quite a lot of neurodegenerative illnesses together with Alzheimer’s and Parkinson’s illnesses, since tubulin is a extremely plentiful protein within the human mind, important for its improvement and performance.

“This was a real collaboration between physics and biology, a really satisfying synergy,” Zanic mentioned, noting that the lab’s researchers span disciplines starting from engineering to cell biology. “With out an interdisciplinary method and the power to simulate the experiment, the analysis would have been a futile try. Computational modeling saved our lab the innumerable experiments that in any other case would have been wanted to pinpoint the particular mixture of proteins that we’ve recognized.”

Simulations predict sturdy plus-end-leading treadmilling within the presence of MAPs. (Arpag*, Lawrence* et al.)

This analysis was funded by Nationwide Institutes of Well being grant R35GM119552, Built-in Organic Programs Coaching in Oncology T32 Coaching Grant CA119925, the American Coronary heart Affiliation Predoctoral Fellowship 19PRE34380083, and Zanic’s Searle Students Program and Human Frontier Science Program Profession Improvement Awards.

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Worldwide collaboration with Vanderbilt scientists sheds

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In collaboration with Australian and Italian geneticists, Vanderbilt College researchers Mukhtar Ahmed, analysis assistant professor of cell and developmental biology, graduate scholar Christian de Caestecker and Ian Macara, professor and chair of the Division of Cell and Developmental Biology, have illuminated a organic course of that allows proteins to maneuver between mobile compartments.

Christian de Caestecker
Christian de Caestecker (Vanderbilt College)
Mukhtar Ahmed
Mukhtar Ahmed (Vanderbilt College)
Ian Macara (Vanderbilt College)

Vital to this transport course of is the exocyst, an eight-protein advanced present in nearly all crops and animals. Lack of perform of any element of the exocyst is deadly in a number of organisms. And, because the researchers have found, particular mutations throughout the exocyst trigger extreme developmental defects in kids.

The findings have been revealed on-line within the article “Mutations within the exocyst element EXOC2 trigger extreme defects in human mind improvement,” within the Journal of Experimental Drugs on July 8.

Nicole Van Bergen, a senior analysis officer at Murdoch Youngsters’s Analysis Institute in Melbourne, initially recognized sufferers with exocyst mutations. She then reached out to Ahmed and Macara to check the impression of those mutation, primarily based on their prior analysis into the exocyst advanced.

The researchers theorized that these mutations allowed for some degree of exocyst perform suitable with life. Nonetheless, the mutations lead to irregular mind and tissue improvement that embody progressive microcephaly, underdeveloped mind areas, epilepsy, facial dysmorphism, congenital cataracts and acute mental incapacity. One of many sufferers that the group adopted died on the age of 10 because of problems arising from these situations.

EXOC2 related neurological disorder
Scientific and mind imaging options of affected sufferers with EXOC2-related neurological dysfunction (Van Bergen and Ahmed et al., 2020)

To grasp the useful penalties of the newly recognized mutations, the Vanderbilt group used excessive pace microscopy and quantitative evaluation to find out that supply of vital proteins to the plasma membrane was decreased by half in cells harboring exocyst mutations. This discount probably causes faulty neuronal outgrowth throughout improvement, an avenue Ahmed and Macara proceed to discover.

“This analysis was a constructive collaboration for us all and has introduced very compelling avenues for future analysis,” mentioned Ahmed, the paper’s co-first creator. “We will now tease out how the exocyst advanced is working throughout the cell and isolate the perform of every of its proteins.”

Viewing vesicle fusions in affected person derived cells throughout time utilizing quick fluorescence microscopy imaging strategies. Every vibrant spot marks the supply of a vesicle to the floor of a single cell. The streaks to the best of every spot present the disappearance of the sign because it spreads away from the supply website.(Mukhtar Ahmed

The analysis was funded by Nationwide Institutes of Well being grant GM070902 in addition to from the Australian Nationwide Well being and Medical Analysis Council.

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Clues to lung damage in preterm infants | VUMC Reporter

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by Leigh MacMillan

Bronchopulmonary dysplasia (BPD) — a type of power lung illness — is a number one complication of preterm beginning affecting infants born earlier than 32 weeks gestation. Publicity to excessive ranges of oxygen (hyperoxia) performs a task in BPD pathogenesis, however the exact molecular mechanisms stay unsure.

Jennifer Sucre, MD, and colleagues beforehand demonstrated a sample of elevated Wnt signaling in human BPD tissue and hyperoxia fashions of BPD. They’ve now used three totally different mannequin methods — 3D human organoids, mouse lung slices and a mouse in vivo mannequin — to outline mediators of activated Wnt signaling after hyperoxia damage.

They found that elevated expression of Wnt5A in lung connective tissue cells contributes to the impaired alveolarization (alveoli are the websites of gasoline trade) and septal thickening noticed in BPD.

The findings, reported within the American Journal of Respiratory and Important Care Drugs, recommend that exact concentrating on of Wnt5A within the lungs of preterm infants could stop or reverse BPD.

This analysis was supported by the Nationwide Institutes of Well being (grants HL143051, CA218526, GM108807, HL101794, HL122626, HL129907, HL133536, HL092870, HL085317, HL128996, HL127173, HL116263, GM122516, HL141380), Division of Veterans Affairs, Francis Household Basis and Julia Carell Stadler Chair in Pediatrics.

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Protein research seeks to induce tumor regression | VUMC Reporter

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by Bill Snyder

MYC is a family of three related proteins that are overexpressed in cancer and which contribute to an estimated 100,000 cancer deaths annually in the United States.

Efforts to block MYC directly have failed. Fortunately, these proteins have an Achilles’ heel — a chromosome-binding cofactor called WDR5.

Understanding how MYC interacts with WDR5 and other cofactors could lead to the development of new drugs that can effectively block MYC and stop many cancers in their tracks.

William Tansey, PhD

Reporting in the Proceedings of the National Academy of Sciences, William Tansey, PhD, and colleagues at Vanderbilt found that disrupting the interaction between MYC and WDR5 in a cancerous growth causes “rapid and comprehensive tumor regression.”

“If the MYC–WDR5 connection is to be pursued as a viable therapeutic avenue, we need to know if breaking this connection in the context of an existing model cancer would have an impact on tumor growth,” said Tansey, co-leader of the Vanderbilt-Ingram Cancer Center’s Genome Maintenance Research Program.

That’s what they did, using a laboratory-grown model of Burkitt’s lymphoma, a form of non-Hodgkin’s lymphoma or immune-cell cancer. “We now know that breaking this connection causes these tumors to disappear,” he said.

Tansey is the Ingram Professor of Cancer Research and professor of Cell & Developmental Biology and Biochemistry.

In 2015, in collaboration with Tansey’s group, a team led by Stephen Fesik, PhD, the Orrin H. Ingram, II Professor of Cancer Research, solved the crystal structure of the MYC-WDR5 interaction. This effort led to their ongoing collaboration to discover drugs that can target MYC through WDR5.

Lance Thomas, PhD, research assistant professor of Cell & Developmental Biology, is the paper’s first author. In addition to Tansey and Fesik, other co-authors are Clare Adams, PhD, Jing Wang, PhD, April Weissmiller, PhD, Joy Creighton, Shelly Lorey, Qi Liu, PhD, and Christine Eischen, PhD.

The research was supported by the National Cancer Institute of the National Institutes of Health, the Robert J. Kleberg and Helen C. Kleberg Foundation, TJ Martell Foundation, St. Baldrick’s Foundation, Alex’s Lemonade Stand Foundation and the Edward P. Evans Foundation.

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Protein research seeks to induce tumor regression | VUMC Reporter

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by Bill Snyder

MYC is a family of three related proteins that are overexpressed in cancer and which contribute to an estimated 100,000 cancer deaths annually in the United States.

Efforts to block MYC directly have failed. Fortunately, these proteins have an Achilles’ heel — a chromosome-binding cofactor called WDR5.

Understanding how MYC interacts with WDR5 and other cofactors could lead to the development of new drugs that can effectively block MYC and stop many cancers in their tracks.

William Tansey, PhD

Reporting in the Proceedings of the National Academy of Sciences, William Tansey, PhD, and colleagues at Vanderbilt found that disrupting the interaction between MYC and WDR5 in a cancerous growth causes “rapid and comprehensive tumor regression.”

“If the MYC–WDR5 connection is to be pursued as a viable therapeutic avenue, we need to know if breaking this connection in the context of an existing model cancer would have an impact on tumor growth,” said Tansey, co-leader of the Vanderbilt-Ingram Cancer Center’s Genome Maintenance Research Program.

That’s what they did, using a laboratory-grown model of Burkitt’s lymphoma, a form of non-Hodgkin’s lymphoma or immune-cell cancer. “We now know that breaking this connection causes these tumors to disappear,” he said.

Tansey is the Ingram Professor of Cancer Research and professor of Cell & Developmental Biology and Biochemistry.

In 2015, in collaboration with Tansey’s group, a team led by Stephen Fesik, PhD, the Orrin H. Ingram, II Professor of Cancer Research, solved the crystal structure of the MYC-WDR5 interaction. This effort led to their ongoing collaboration to discover drugs that can target MYC through WDR5.

Lance Thomas, PhD, research assistant professor of Cell & Developmental Biology, is the paper’s first author. In addition to Tansey and Fesik, other co-authors are Clare Adams, PhD, Jing Wang, PhD, April Weissmiller, PhD, Joy Creighton, Shelly Lorey, Qi Liu, PhD, and Christine Eischen, PhD.

The research was supported by the National Cancer Institute of the National Institutes of Health, the Robert J. Kleberg and Helen C. Kleberg Foundation, TJ Martell Foundation, St. Baldrick’s Foundation, Alex’s Lemonade Stand Foundation and the Edward P. Evans Foundation.

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Microscopic spines join worm neurons | VUMC Reporter

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by Leigh MacMillan

Dendritic “spines” — small protrusions on the receiving aspect of the connection (synapse) between two nerve cells — are acknowledged as key purposeful elements of neuronal circuits in mammals. The shapes and numbers of spines are regulated by neuronal exercise and correlate with studying and reminiscence.

Though spine-like protrusions have been reported within the nervous system of the invertebrate worm C. elegans, it isn’t identified if these buildings share purposeful options with vertebrate dendritic spines.

Now, Andrea Cuentas-Condori, Sierra Palumbos, David Miller, PhD, and colleagues have used super-resolution microscopy, electron microscopy, live-cell imaging and genetics to characterize spine-like buildings on C. elegans motor neurons. They report within the journal eLife that C. elegans spines are dynamic buildings that sense and reply to neuronal exercise, like their mammalian counterparts.

The research set up the genetically tractable and clear C. elegans as a mannequin organism for the research of dendritic backbone formation and performance. Reside-cell imaging research and unbiased genetic screens ought to pace the invention of genes that regulate backbone biology.

This analysis was supported by the Nationwide Institutes of Well being (grants NS081259 and NS106951), the American Coronary heart Affiliation, the Nationwide Science Basis and the Canadian Institute of Well being Analysis.

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Microvilli in movement | VUMC Reporter

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by Anivarya Kumar

The Sept. 9 difficulty of Developmental Cell featured the analysis of Matthew Tyska and colleagues on the duvet. The picture reveals microvillar actin protrusions with colours indicating depth relative to the cell floor.

Microvilli are protrusions on the floor of epithelial cells which can be devoted to mechanosensation within the inside ear, and chemosensation and solute uptake within the lungs, intestine, gut and urinary tract. Epithelial cells assemble dense arrays of microvilli known as “brush borders” that defend towards infections and harm.

Leslie Meenderink, MD, PhD, Matthew Tyska, PhD, and colleagues used reside cell imaging to visualise early steps of brush border formation.

They discovered that particular person microvilli exhibit persistent lively motility. Pushed by actin meeting on the barbed ends of core bundles, microvilli motility permits the protrusions to collide and cluster into extremely organized arrays.

The analysis, featured on the duvet of the Sept. 9 difficulty of Developmental Cell, factors to microvillar motility as a beforehand unrecognized driving pressure for apical floor reworking and maturation throughout epithelial differentiation. These findings present additional perception into the morphogenesis of a number of organ programs.

This analysis was supported by the Nationwide Institutes of Well being (grants AI007474, GM008554, HD007502, GM008320, DK111949, DK095811).

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A “rheostat” for most cancers alerts | VUMC Reporter

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by Sanjay Mishra

WNT signaling pathways play necessary roles in cell development, improvement and most cancers.The classical or “canonical” WNT pathway and its atypical, “non-canonical” counterpart share a protein referred to as DVL2 that “transduces” or converts one form of sign to a different.

Now Jason MacGurn, PhD, and colleagues have proven that two different proteins, USP9X and WWP1, act on DVL2 to control each WNT signaling pathways.

Whereas WWP1 suppresses DVL2 by tagging it with a protein referred to as ubiquitin that marks it for degradation, USP9X promotes WNT activation by releasing DVL2 from ubiquitin and rescuing it from degradation.

These antagonistic interactions set up a ubiquitylation “rheostat” on DVL2 that may be a important regulator of WNT pathway specification in human breast most cancers cells, and which directs its participation in both WNT pathway, the researchers reported within the journal Cell Experiences.

These findings have necessary implications for therapeutic concentrating on of WNT pathways in human most cancers.

This analysis was supported by the Nationwide Institutes of Well being (grants GM101077 and CA095103).

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The plus and minus of microtubules | VUMC Reporter

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by Bill Snyder

The September issue of the Journal of Cell Biology featured the research of Marija Zanic and colleagues on the cover. The image is a montage of dynamic microtubule extensions (teal) grown in vitro from stabilized microtubule seeds (red).

Microtubules are protein polymers that assemble into dynamic structures, essential for cell division, shape, motility, and transport of intracellular cargos.

Proteins that regulate microtubule function and activity have been implicated in disorders ranging from Alzheimer’s disease to cancer. By learning how microtubules work, scientists hope to find new ways to treat these diseases.

The “plus” and “minus” ends of microtubules switch between growing and shrinking, a phenomenon known as “dynamic instability.” Now Marija Zanic, PhD, and colleagues have discovered that the distinct rate at which tubulin protein subunits dissociate (the tubulin “off-rate”) underlies key dynamic differences between the two ends.

The researchers also found that a minus-end directed motor protein, the human kinesin-14 HSET, promotes minus-end stability by suppressing the minus-end tubulin “off-rate,” even when challenged by the de-stabilizing kinesin-13 MCAK motor.

Their report, published in the September issue of the Journal of Cell Biology and featured on the cover, suggests that regulation of both the plus and minus microtubule ends is integrated to form the basis for the dynamic architecture of cellular microtubules.

This research was supported by the National Institutes of Health (grants GM119552, GM086610, GM008554), the Human Frontier Science Program and the Searle Scholars Program.

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New position for microtubules in diabetes | VUMC Reporter

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by Invoice Snyder

The failure of pancreatic beta cells to launch acceptable quantities of insulin in response to rising blood glucose ranges is a trademark of sort 2 diabetes.

Through the previous decade researchers have proven that microtubules — a part of the cell’s cytoskeleton — play an essential position in regulating the supply of insulin granules to the cell membrane for secretion. Now Kathryn Trogden, PhD, and colleagues report that microtubules are also essential for the biogenesis of the granules themselves.

Microtubules, it seems, are extremely regulated by glucose appearing by way of the ever-present messaging molecule cyclic AMP and its effector protein EPAC2. The glucose sign causes microtubules to disassemble and reassemble on the Golgi equipment contained in the cell, the place insulin granules are fashioned.

Inhibiting EPAC2 blocked formation of recent Golgi-derived microtubules and in the end resulted in depletion of insulin granules within the beta cell, the researchers reported this month within the journal Present Biology.

Their findings present additional proof that regulating microtubule dynamics could also be a possible new method to treating diabetes.

This analysis was supported by the Nationwide Institutes of Well being (grants DK007061, DK117529, GM127098, DK065949, DK106228).

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