Groundbreaking discoveries from the 29th Genetic Society's Mammalian Genetics and Development Workshop
November 29, 2018 • UCL Great Ormond Street Institute of Child Health
In the heart of London, at the forefront of genetic discovery, researchers gathered at the UCL Great Ormond Street Institute of Child Health on November 29, 2018, for the 29th Genetic Society's Mammalian Genetics and Development Workshop. This annual meeting served as a vibrant platform for scientists to share groundbreaking research on how genes guide the development of mammals and influence disease 1 8 .
The findings presented here are not just about isolated laboratory studies; they represent significant leaps in understanding human health, from the mysteries of dementia to the origins of childhood tumors and the mechanisms behind birth defects.
UCL Great Ormond Street Institute of Child Health, London
November 29, 2018
Individuals with Down syndrome carry an extra copy of chromosome 21. This chromosome contains the APP gene, which is responsible for producing amyloid beta—the main component of brain plaques found in Alzheimer's disease 1 4 .
Researchers are using a mouse model of Down syndrome to investigate whether other triplicated genes on chromosome 21 also contribute to Alzheimer's pathology. Their work focuses on APP processing in specialized cellular compartments called endosomes.
Cornelia de Lange Syndrome (CdLS) is a developmental disorder often accompanied by cognitive impairment, caused by mutations in the cohesin complex. This complex helps organize the 3D structure of our genome 1 4 .
This reveals that cohesin is not just a developmental architect but a constant sustainer of neuronal gene expression, opening new avenues for understanding and treating neuronal dysfunction in CdLS.
| Research Focus | Key Finding | Scientific and Clinical Significance |
|---|---|---|
| Alzheimer's & Down Syndrome | Genes beyond APP on chromosome 21 contribute to altered APP processing. | Identifies new therapeutic targets for dementia in Down syndrome. |
| Cohesin Function | Cohesin is continuously required in mature neurons to sustain gene expression. | Re-frames understanding of cognitive impairment in Cornelia de Lange Syndrome. |
| Epigenetic Reversion | Mutant gene expression can be naturally silenced, reversing a disease phenotype. | Validates allele-specific silencing as a viable therapeutic strategy. |
| Craniopharyngioma Tumors | Senescent "zombie" cells drive tumor formation non-cell-autonomously via SASP. | Reveals a novel mechanism of tumorigenesis, suggesting senolytic therapies. |
| Neural Tube Closure | ROCK-dependent apical constriction is coordinated with the cell cycle. | Provides insight into the fundamental mechanisms preventing birth defects. |
One of the most striking discoveries presented was that of epigenetic revertant mosaicism in patients with congenital melanocytic naevi (CMN). These are dark skin patches caused by spontaneous NRAS gene mutations before birth 1 4 .
Patients developed new islands of perfectly normal skin within their naevi. Intriguingly, biopsies showed that the skin cells in these normal patches still carried the original NRAS mutation in their DNA.
The difference was not in the gene itself, but in its expression. In the normal skin, the body had somehow silenced the mutant copy of the gene, allowing only the healthy copy to be active. This occurred without changing the underlying DNA sequence—a process known as epigenetic regulation.
A crucial process in early development is the closure of the neural tube, which later forms the brain and spinal cord. Failure of this process leads to severe birth defects like spina bifida. A key mechanical force driving neural tube closure is apical constriction, where the tops of neuroepithelial cells contract to help bend the tissue. This force must be perfectly coordinated with interkinetic nuclear migration (IKNM), the rhythmic movement of cell nuclei as they progress through the cell cycle 1 4 .
To unravel this coordination, researchers designed a series of elegant experiments:
The results revealed a sophisticated temporal coordination between cell mechanics and the cell cycle:
| Cell State / Experimental Condition | Effect on Apical Cell Area | Biological Interpretation |
|---|---|---|
| Cells entering G1 (pRB+), Vehicle | Small apical area | ROCK activity maintains constriction after mitosis. |
| Cells entering G1 (pRB+), ROCK inhibited | Significantly larger apical area | Loss of ROCK prevents maintenance of constriction. |
| Cells in M-phase (pHH3+), Vehicle | Wide range of areas | Constriction during mitosis is complex. |
| Cells in M-phase (pHH3+), ROCK inhibited | No significant change | Mitotic constriction is ROCK-independent. |
| Cells trapped in S-phase | Prevents neural tube widening | Progression through cell cycle enables ROCK-dependent constriction. |
The breakthroughs presented at the workshop rely on a sophisticated array of research tools and reagents. Here are some essentials used in modern genetics and developmental biology 1 4 7 :
Inhibits Rho-associated kinase, disrupting actomyosin contractility.
Example: Studying cellular forces in neural tube closure
Models human genetic conditions like Down syndrome for mechanistic studies.
Example: Investigating APP processing and Alzheimer's pathology
Precisely edits DNA sequences to create specific mutations or insertions.
Example: Generating mouse models with segmental duplications
Enzyme for Polymerase Chain Reaction (PCR), amplifying specific DNA sequences.
Example: Genotyping genetically modified mice
Protease and phosphatase inhibitor cocktails that protect protein samples.
Example: Maintaining protein integrity during analysis
Enzymes that break down collagen, dissociating tissues into single cells.
Example: Isolating specific cell populations from tissues
By deciphering the intricate dance of genes, cells, and forces that build a healthy organism, scientists are not only solving deep biological mysteries but also illuminating new paths for therapy. From the natural epigenetic silencing of a mutant gene to the constant role of cohesin in our neurons, these findings provide the crucial blueprints for building the next generation of treatments for genetic disorders, dementia, and cancer.
The journey from a London workshop to a future therapy is long, but it is fueled by these very moments of scientific insight and collaboration.
These discoveries highlight how understanding basic biological mechanisms can lead to transformative medical advances, offering hope for treating complex genetic conditions.