Immunostaining for different cortical layer markers. Credit: The Jackson Laboratory
Researchers from The Jackson Laboratory (JAX) developed a novel platform to study how the same mutation within a gene can result in different outcomes. The platform will assist with developing new therapeutic targets and enhance the ability to study diseases within the context of genetic diversity.
The platform, published in Science Advances, mimics human genetic diversity by using stem cells from eight different mouse strains. Using the tool the team investigated the DYRK1A gene, a gene associated with autism, microcephaly, and intellectual disability in humans, ultimately discovering that inhibiting the gene with the mouse stem cells led to different effects in the growth and repair of neurons. The findings provide new insights into what may lead to resistance or vulnerability to autism development.
“If we studied one strain, we wouldn’t have seen this incredible degree of variation,” said Professor Martin Pera. “But by studying eight, we showed that stem cell models in a dish can accurately predict an individual’s sensitivity or resilience to disease-causing mutations, in this case an autism syndrome disorder. Careful comparison of sensitive and resilient mouse strains at the cellular level also enabled us to identify potential targets for therapeutic intervention.”
During the development of the platform, the team discovered that only the stem cells from mouse strain 129S1/SvlmJ (129) could be used to differentiate into neurons using traditional protocols. To remedy this, the team developed new protocols that worked across all eight strands and efficiently produced multiple neuron types.
Further analysis revealed that C57BL/6J (B6) most closely modeled human iPSC response to low DYRK1A levels, while the least affected strains were WSB/EiJ (WSB) and NZOHiLtJ (NZO). further analysis using live mice to study B6 susceptibility found that the loss of just one copy of DYRK1A resulted in no live offspring with a B6 background while others such as 129 were unaffected. Crossing B6 and 129 resulted in living offspring with clinical features associated with DYRK1A mutations in humans.
“This work illustrates the power of incorporating genetic diversity into disease models,” said Pera. “The use of stem cells in vitro allows us to directly compare mouse and humans, and to bridge results in a petri dish to those in a whole organism. The approach will have wide application in disease genetics and will enhance and accelerate precision disease modeling in the mouse.”