A new study led by researchers at Baylor College of Medicine revealed how in utero Zika virus infection can lead to microcephaly in newborns. The team discovered that the Zika virus protein NS4A disrupts brain growth by hijacking a pathway that regulates the generation of new neurons. The findings point at the possibility of developing therapeutic strategies to prevent microcephaly linked to Zika virus infection. The study appeared Thursday in the journal Developmental Cell.
Patients with rare genetic mutations shed light on how Zika virus causes microcephaly
The current study was initiated when a patient presented with a small brain size at birth and severe abnormalities in brain structures at the Baylor Hopkins Center for Mendelian Genomics (CMG), a center directed by Dr. Jim Lupski, professor of pediatrics, molecular and human genetics at Baylor College of Medicine and attending physician at Texas Childrens Hospital, said Dr. Hugo J. Bellen, professor at Baylor, investigator at the Howard Hughes Medical Institute and Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital.
This patient and others in a cohort at CMG had not been infected by Zika virus in utero. They had a genetic defect that caused microcephaly. CMG scientists determined that the ANKLE2 gene was associated with the condition. Interestingly, a few years back the Bellen lab had discovered in the fruit fly model that ANKLE2 gene was associated with neurodevelopmental disorders. Knowing that Zika virus infection in utero can cause microcephaly in newborns, the team explored the possibility that Zika virus was mediating its effects in the brain via ANKLE2.
In a subsequent fruit fly study, the researchers demonstrated that overexpression of Zika protein NS4A causes microcephaly in the flies by inhibiting the function of ANKLE2, a cell cycle regulator that acts by suppressing the activity of VRK1 protein.
Since very little is known about the role of ANKLE2 or VRK1 in brain development, Bellen and his colleagues applied a multidisciplinary approach to tease apart the exact mechanism underlying ANKLE2-associated microcephaly.
The fruit fly helps clarify the mystery
The team found that fruit fly larvae with mutations in ANKLE2 gene had small brains with dramatically fewer neuroblasts brain cell precursors and could not survive into adulthood. Experimental expression of the normal human version of ANKLE2 gene in mutant larvae restored all the defects, establishing the loss of Ankle2 function as the underlying cause.
To understand why ANKLE2 mutants have fewer neuroblasts and significantly smaller brains, we probed deeper into asymmetric cell divisions, a fundamental process that produces and maintains neuroblasts, also called neural stem cells, in the developing brains of flies and humans, said first author Dr. Nichole Link, postdoctoral associate in the Bellen lab.
Asymmetric cell division is an exquisitely regulated process by which neuroblasts produce two different cell types. One is a copy of the neuroblast and the other is a cell programmed to become a different type of cell, such as a neuron or glia.
Proper asymmetric distribution and division of these cells is crucial to normal brain development, as they need to generate a correct number of neurons, produce diverse neuronal lineages and replenish the pool of neuroblasts for further rounds of division.
When flies had reduced levels of Ankle2, key proteins, such as Par complex proteins and Miranda, were misplaced in the neuroblasts of Ankle2 larvae. Moreover, live imaging analysis of these neuroblasts showed many obvious signs of defective or incomplete cell divisions. These observations indicated that Ankle2 is a critical regulator of asymmetric cell divisions, said Link.
Further analyses revealed more details about how Ankle2 regulates asymmetric neuroblast division. They found that Ankle2 protein interacts with VRK1 kinases, and that Ankle2 mutants alter this interaction in ways that disrupt asymmetric cell division.
The Zika connection
Linking our findings to Zika virus-associated microcephaly, we found that expressing Zika virus protein NS4A in flies caused microcephaly by hijacking the Ankle2/VRK1 regulation of asymmetric neuroblast divisions. This offers an explanation to why the severe microcephaly observed in patients with defects in the ANKLE2 and VRK1 genes is strikingly similar to that of infants with in utero Zika virus infection, Link said.
Subscribe to Outbreak News TV
For decades, researchers have been unsuccessful in finding experimental evidence between defects in asymmetric cell divisions and microcephaly in vertebrate models. The current work makes a giant leap in that direction and provides strong evidence that links a single evolutionarily conserved Ankle2/VRK1 pathway as a regulator of asymmetric division of neuroblasts and microcephaly, Bellen said.
Moreover, it shows that irrespective of the nature of the initial triggering event, whether it is a Zika virus infection or congenital mutations, the microcephaly converges on the disruption of Ankle2 and VRK1, making them promising drug targets.
Another important takeaway from this work is that studying a rare disorder (which refers to those resulting from rare disease-causing variations in ANKLE2 or VRK1 genes) originally observed in a single patient can lead to valuable mechanistic insights and open up exciting therapeutic possibilities to solve common human genetic disorders and viral infections.
- There is a strong genetic component to asthma, but it's not the only risk factor - Insider - INSIDER - July 12th, 2020
- Alzheimer's disease: protective gene uncovered in human cell model bringing promise for new drug discoveries - The Conversation UK - July 12th, 2020
- Four Rivers Wildlife: The color of my skin - Murray Ledger and Times - July 12th, 2020
- How Could Human Nature Have Become This Politicized? - The New York Times - July 12th, 2020
- Gaucher Disease Treatment Market 2016 Analysis, Types, Applications, Forecast 2028 - Jewish Life News - July 12th, 2020
- World-Renowned Transplant Surgeon to Lead Department of Surgery at NYU Langone Health - NYU Langone Health - July 12th, 2020
- 30% South Asians have Neanderthal gene that increases risk of severe Covid-19: Study - ThePrint - July 12th, 2020
- What's the science on DNA and RNA vaccines? - DW (English) - July 12th, 2020
- The Clock Is Ticking: Can Mankind Beat the Extinction? - Interesting Engineering - July 12th, 2020
- New Report: Genomic Biomarker Market: Reporting and Evaluation of Recent Industry Developments| Bio-Rad, Beckman Coulter, Myriad Genetics, Thermo... - July 12th, 2020
- Efforts to beat the coronavirus pandemic could cause over 1 million extra deaths from other diseases, experts warn - CNN - July 12th, 2020
- 10-year plan hopes to give western chimpanzees a fighting chance - Mongabay.com - July 12th, 2020
- Explained: A new calculation to find out your dogs age in human years - The Indian Express - July 12th, 2020
- Scores forecast effects of mutations in autism gene - Spectrum - July 10th, 2020
- Herd Immunity Is A Distant Dream- Antibodies May Disappear From An Individual's Body Within Weeks - Inventiva - July 10th, 2020
- Explained: A new calculation to find your dogs age in human years - The Indian Express - July 10th, 2020
- SETI in the News Media Roundup May 16 June 30, 2020 - SETI Institute - July 10th, 2020
- Idorsia announces positive results in the second Phase 3 study of daridorexant - GlobeNewswire - July 10th, 2020
- Human genetics - Wikipedia - June 22nd, 2020
- human genetics | Description, Chromosomes, & Inheritance ... - June 22nd, 2020
- Human Genetics - David Geffen School of Medicine at UCLA - June 22nd, 2020
- Genetic Mutations as a Tool To Predict Lifespan and Fertility - Technology Networks - June 22nd, 2020
- Human Genetics Market Analysis with Key Players, Applications, Trends and Forecasts to 2026 - Farmers Ledger - June 22nd, 2020
- China Is Collecting DNA From Tens of Millions of Men and Boys, Using U.S. Equipment - The New York Times - June 22nd, 2020
- Researchers identify environmental components that affect gene expression in cardiovascular disease - The South End - June 22nd, 2020
- China collects DNA from millions of men and boys - BioNews - June 22nd, 2020
- Exposure and engagement with tobacco-related social media and associations with subsequent tobacco use among young adults: A longitudinal analysis. -... - June 22nd, 2020
- COVID-19 Test Samples: Why Do We Swab Instead of Spit? - The Wire - June 22nd, 2020
- Coronavirus news and updates: Does Florida's spike in cases make it a new 'epicenter'?; mask rules on airplanes from the FAA - USA TODAY - June 22nd, 2020
- The beauty of flaws - NCC Linked - June 22nd, 2020
- Study finds genetic factors that make some more susceptible to Covid-19 - Health24 - June 22nd, 2020
- Assessment of COVID-19's Effect on Precision Medicine Software Market 2020-2024 | Benefits of Precision Medicine to Augment Growth | Technavio -... - June 22nd, 2020
- Wellness Experts Discuss The Importance Of Individualizing Your Approach To Health - Forbes - June 22nd, 2020
- 1.4 million for genetics research on how obesity in pregnancy affects mother and baby - Mirage News - June 9th, 2020
- Aerpio Hosting Key Opinion Leader Call on a Novel Mechanism for the Treatment of Glaucoma - GlobeNewswire - June 9th, 2020
- Amgen To Present At The Goldman Sachs 41st Annual Global Healthcare Conference - Monterey County Weekly - June 9th, 2020
- COVID-19 Pandemic: Global Risks of More Complex Character and the Visions of the Future World - Valdai Discussion Club - May 19th, 2020
- Rothamsted turn to harvesting coronavirus data - Lab News - May 19th, 2020
- Complement genes add to sex-based vulnerability in lupus and schizophrenia - UAB News - May 19th, 2020
- DU to set up School of Public Health - The Indian Express - May 19th, 2020
- Covid-19 research: 45 Bengaluru startups working on medicine, testing methods and vaccine - Economic Times - May 19th, 2020
- Immortalized Cell Line Market Development, Trends, Key Driven Factors, Segmentation And Forecast to 2020-2026 - Cole of Duty - May 19th, 2020
- Worlds Shortest Population Reveal the Largest Genetic Contributor to Height - Technology Networks - May 15th, 2020
- Group of Genes Have Altered Expression in Autism - Technology Networks - May 15th, 2020
- Why can two young and healthy individuals be affected so differently by coronavirus? - Health24 - May 15th, 2020
- Amgen To Present At The Bank Of America Merrill Lynch Virtual Global Healthcare Conference - BioSpace - May 15th, 2020
- Viewpoint: Darwin's 'Descent of Man' is both deeply disturbing and more relevant than ever - Genetic Literacy Project - May 15th, 2020
- Study Finds Low Proportion of Individuals With Autism Receive Recommended Genetic Tests - Technology Networks - May 15th, 2020
- Cats can catch Covid-19 from other cats. The question is: Can we? - STAT - May 15th, 2020
- Deficient Expression of DGCR8 in Human Testis is Related to Spermatoge | IJGM - Dove Medical Press - May 15th, 2020
- Prevail Therapeutics Reports First Quarter 2020 Financial Results and Business Highlights - GlobeNewswire - May 15th, 2020
- Fulcrum Therapeutics, Inc. (FULC) Q1 2020 Earnings Call Transcript - The Motley Fool - May 15th, 2020
- Scientists concerned that coronavirus is adapting to humans - The Guardian - May 11th, 2020
- Coronavirus quickly spread around the world starting late last year, new genetic analysis shows - CNN - May 11th, 2020
- Your genes could determine whether the coronavirus puts you in the hospital and we're starting to unravel which ones matter - The Conversation US - May 11th, 2020
- Yes, COVID-19 is mutating, here's what you need to know - ABC News - May 11th, 2020
- Conservatives Are Not the Only Ones Who Ignore Facts and the Science - Merion West - May 11th, 2020
- Coronavirus in Scotland: Charity warns Covid will cause a spike in ME cases - as it calls for 'harmful' exercise treatment to be banned -... - May 11th, 2020
- Dr. Misaki Wayengera: The Man Behind Uganda's Covid 19 Test Kits - New Vision - May 11th, 2020
- Its In The Genes? Scientists Think Coronavirus Exploits Silent Hidden Mutations In The Body - International Business Times - May 11th, 2020
- From blood clots to 'Covid toe': Experts confounded by series of medical mysteries - The Straits Times - May 11th, 2020
- MET 2020 Slot booking to commence on July 15, Examination dates available at manipal.edu - Jagran Josh - May 11th, 2020
- Vitagene Launches The First FDA Authorized Saliva based Zero Contact COVID-19 At Home Test - Business Wire - May 10th, 2020
- Genetics in focus after coronavirus deaths of siblings and twins - The Guardian - May 10th, 2020
- 'An anvil on my chest': What it's like to have COVID-19 - LancasterOnline - May 10th, 2020
- Coronavirus may have spread to humans as early as October 2019 - study - The Jerusalem Post - May 10th, 2020
- Team reveals genomic history of ancient civilizations in the Andes - UC Santa Cruz - May 10th, 2020
- Regeneron Reports First Quarter 2020 Financial and Operating Results - BioSpace - May 10th, 2020
- Scientists at Ben-Gurion University of the Negev Develop Anti-Coronavirus Surface Coating Based on Nanomate... - The Auto Channel - May 10th, 2020
- COVID-19 and food security - Fitzwilliam College, University of Cambridge - May 10th, 2020
- Val Sheffield elected to the American Academy of Arts and Sciences - Iowa Now - May 1st, 2020
- DNA gives clues into risk of developing Alzheimer's disease and other dementias - Alabama NewsCenter - May 1st, 2020
- Rare Gene Discovered That Nearly Doubles Risk of Developing a Neurodegenerative Disease - Clinical OMICs News - May 1st, 2020
- Progress in understanding the genetic basis of mental health - SFARI News - May 1st, 2020
- Coronavirus was widespread in UK at very start of pandemic, says genetics expert - Sky News - May 1st, 2020
- This is how you do the genetics heritage filter on Instagram that everyone's doing - The Tab - May 1st, 2020
- COVID-19 vaccine in Ireland could take a year and a half - IrishCentral - May 1st, 2020
- MRC scientists elected Fellows of the Royal Society - Cambridge Network - May 1st, 2020
- Parkinson's discovery implicates "second brain" in the gut - New Atlas - May 1st, 2020
- Humans: are we the most effective vector of disease? - BugBitten - BMC Blogs Network - May 1st, 2020