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How does the intricately complex brain develop? And what is it that goes wrong in disorders such as cerebral palsy or pediatric brain tumors?

“If our brains were simple enough for us to understand them, we’d be so simple that we couldn’t.” (Ian Stewart). One of the driving forces in the lab is to try to understand how specific cells, structures, or systems develop in the brain. Deregulation of brain development can result in developmental disorders with motor and/or cognitive defects, or brain cancer.In order to answer these questions, we use high through-put in vivo approaches to identify genetic components contributing to brain development. We also have collaborations in place to perform whole-exome sequencing from patient materials to identify genes mutated in specific disorders.

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How does abrogated Notch signaling result in Alagille syndrome?

Alagille syndrome is diagnosed based on bile duct paucity, heart defects, characteristic facial features, butterfly vertebrae and posterior embryotoxon, followed by genetic confirmation of JAGGED1 (JAG1) or NOTCH2 mutations. However, other symptoms, including spontaneous vascular accidents and kidney dysfunction, pose significant problems for patients. Elucidating JAG1/NOTCH2-driven molecular and developmental processes will allow us to narrow down the best therapeutic approaches.

Bringing together epidemiological analyses, Alagille patient samples, an Alagille mouse model, and high-throughput in vivo and in vitro assays, we aim to answer:

  1. How does Notch regulate biliary tubule formation during development?
  2. Why do Alagille patients die from intracranial bleeds?
  3. Can disease course be predicted based on specific symptoms?
  4. Which treatment forms are best suited to tackling Alagille syndrome?

For more info, see Masek & Andersson Development 2017

Masek & Andersson Figure 4 opaque v3