Clues into common pathology can start from human genetic disorders. As the first step to finding potential therapeutics, we use genetics to determine molecular mechanisms of pediatric disorders.
Ion Channels in Morphological Development
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We have identified a potential therapeutic target for fetal alcohol syndrome by studying a rare genetic disorder that has the same spectrum of congenital birth defects as FASD. The genetic disorder, (Andersen Tawil Syndrome) is caused by genetic disruption of a potassium channel. This potassium channel is blocked in the presence alcohol. Research in the Bates lab has determined that this potassium channel is needed for canonical Bone Morphogenetic Protein (BMP) signaling from flies to mice. We now use both flies and mice to determine which ion channels contribute to developmental signaling.
This is exciting because ion channels are readily targeted pharmacologically. This presents the possibility that ion channels could be manipulated to influence cell fate choices to generate specific tissues like cartilage or bone. For these potential applications, we explore the role of ion flux in development. |
Alcian and Alziran cartilage and bone staining of Ki2.1 Flox'd mouse skull
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CBD Consumption During Pregnancy and Brain Development
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Many people suffer from nausea and vomiting during pregnancy which is commonly called morning sickness. One of the up-and-coming supplements now being consumed to decrease this nausea and vomiting is cannabidiol, or CBD. However, they are very few studies looking at how CBD consumption during pregnancy effects fetal development or postnatal behavior.
We are currently studying how CBD consumption during pregnancy effects development of an area of the brain called the hypothalamus at a transcriptional level using single cell RNA sequencing. Additionally, we are investigating how CBD exposure effects postnatal behavior. This is critical no matter the results because if CBD shows harm, we will be able to inform clinicians to discourage CBD use during pregnancy. If CBD does not show harm, it opens a pathway for clinical studies looking at CBD use to decrease morning sickness. |
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Cytoskeleton in Brain Development
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Cells require a cytoskeleton to be drastically remodeled during development, but stable in adulthood. An extreme example of the profound changes required of the cytoskeleton is neuronal migration and axonogenesis. We use mutations that disrupt components of the cytoskeleton to understand how cytoskeleton function impacts brain development. Specifically, we model mutations that were derived from patients with developmental brain disorders in rodent neurons to understand how the mutations impact morphology of a neuron, the dynamic changes in the cytoskeleton, and ultimately the structure of the brain.
We recently used a multi-system approach to show that a mutation in mouse Tuba1a (Tuba1aND) destabilizes the αβ heterodimer to disrupt the normal blend of tubulin isotypes, leading to defects in cortical layering and innervation of limbs (Hansen et al, 2016). Neurons in Tuba1aND embryos exhibit specific defects in axon architecture, including delayed axon extension and changes in tubulin posttranslational modifications in the growth cone. These mice also have adult onset ataxia and motor deficits showing that Tuba1a is important for post-natal brain function. Our results point to an important role for TUBA1A in the axon, and we are now poised to elucidate the underlying mechanism and whether this mechanism depends on unique coding or non-coding features of this α-tubulin isotype. Our goal is to understand how the cytoskeleton is regulated to form specific cellular structures and perform specific functions in neurons. |
Axon Migration
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