The Gergely Lab

Our recent publications:

Myeloid cell interferon secretion restricts Zika flavivirus infection of developing and malignant human neural progenitor cells (September 2022)

For continuation of our Zika theme, check out our latest paper here in Neuron! With our collaborators David Rowitch and Harry Bulstrode we unveil an important non-cell-autonomous role for microglia in protecting brain cells against Zika infection.

Lab members (past and present) who contributed: Tannia Gracia and Gemma Girdler

Centrosome function is critical during terminal erythroid differentiation (June 2022)

Studying centrosome function in blood development has revealed some interesting cell type-specific requirements for centrosomes in mitosis. If you are interested, clink on this link to our recent paper!

Lab members (past and present) who contributed: Peter Tatrai

Accessorizing the centrosome: new insights into centriolar appendages and satellites (Nov 2020)

If you want to know more about centrosomal substructures, read our recent review here.

A high-content RNAi screen reveals multiple roles for long noncoding RNAs in cell division (April 2020)


Click here to access the original paper in Nature Communications by Lovorka Stojic et al. This was yet again a fantastic collaboration with the Bakal, Marioni and Odom labs.

Centriolar satellites are acentriolar assemblies of centrosomal proteins (June 2019)

Click here to access the original paper in the EMBO Journal by Valentina Quarantotti et al. Jia-Xuan (aka Jimmy) Chen from the Miller lab (and now at IMB, Meinz) was instrumental to our data analysis.

Centriolar satellites are cytoplasmic membraneless granules implicated in centrosome and primary cilia function. Although several satellite components have been identified previously, a comprehensive survey of satellite content was lacking. We performed proteomic profiling of satellites and revealed over 200 satellite-associating proteins including structural and regulatory components. Our data reveals a substantial overlap with the centrosome proteome both in normal and acentriolar cells. In fact, we have identified over half of all known centrosomal proteins in these structures.

Specificity of RNAi, LNA and CRISPRi as loss-of-function methods in transcriptional analysis (July 2018)

Click here to access the original paper in Nucleic Acid Research by Lovorka Stojic and Aaron Lun et al. This work has resulted from our longstanding collaboration with the Marioni and Odom labs at CRUK CI.

Disease-associated mutations in CEP120 destabilize the protein and impair ciliogenesis (May 2018)

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Click here to access the original paper in Cell Reports by Nimesh Joseph et al. This work is born from a great ongoing collaboration with the van Breugel lab at the MRC-LMB in Cambridge.

Ciliopathies are a group of genetic disorders caused by a failure to form functional cilia. Due to a lack of structural information it is currently poorly understood how ciliopathic mutations affect protein functionality to give rise to the underlying disease. Using X-ray crystallography the van Breugel lab showed that the ciliopathy-associated centriolar protein CEP120 contains three C2 domains. The point mutations V194A and A199P, which cause Joubert syndrome (JS) and Jeune asphyxiating thoracic dystrophy (JATD), respectively, both reduce the thermo-stability of the second C2 domain by targeting residues that point towards its hydrophobic core. By genome engineering cells to contain these exact mutations, Nimesh found that both mutations caused a reduction in  CEP120 protein levels. Although the mutant versions of CEP120 still supported centriole duplication, they compromised the recruitment of distal centriole markers and cilia formation. Our results provide insights into the disease mechanism of two ciliopathic mutations in CEP120, identify putative binding partners of CEP120 C2B and suggest a complex genotype-phenotype relation of the CEP120 ciliopathy alleles.

New molecular insights into why neural stem cells are sensitive to Zika infection (July 2017)

Click here to access the original paper in Science by Pavithra Chavali, Lovorka Stojic et al.

It takes the coordinated action of many genes to grow a healthy human brain with much of the responsibility lying with stem cells of the developing nervous system. Inherited mutations in genes that lead to loss of these cells cause a rare human genetic condition that manifests in small brain or microcephaly. The recent Zika virus outbreak in Brazil coincided with a massive increase in babies born with microcephaly, but why Zika virus preferentially targets the brain stem cell population has remained a mystery.

In this new study we find that similarly to their rodent counterparts human brain stem cells rely on a gene product called Musashi-1 to supply the large numbers of neurons required for normal brain growth. Indeed, children who carry a mutated form of Musashi-1 have a form of inherited microcephaly. Understandably, brain stem cells produce large quantities of Musashi-1 to sustain their normal developmental program. However, when it comes to infection by Zika virus, we have discovered that Musashi-1 turns into the Achilles’ heel of this cell population. In fact, Zika virus replicates much faster in cells that contain Musashi-1 than in those lacking this gene product. Rapid viral replication leads to virus overload of cells, often culminating in their death. Zika therefore preferentially kills cells with high Musashi-1 levels, which in the human embryo correspond to neural stem cells. This is bad enough, but the story has an additional twist.

We have also found that Musashi-1 protein binds the genome of the Zika virus, and the virus essentially prevents Musashi-1 from performing its normal cellular roles. As a result, even if a brain stem cell does not die of the infection, by using Musashi-1 for its own purpose, the virus will interfere with the normal developmental program of these cells, leading to a reduction in neurons produced and microcephaly.