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Siegenthaler Lab

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Assistant Professor Dr. Julie Siegenthaler has focused much of her research career on understanding how the mammalian brain is formed. As a graduate student in the Department of Neuroscience and Physiology at SUNY Upstate Medical University, Dr. Siegenthaler centered her studies on understanding why maternal alcohol consumption negatively affects growth of the fetal brain. She zeroed in on specific signaling pathways, like transforming growth factor-β, that normally help instruct young neurons to differentiate and migrate to their proper location in a region of the brain called the cerebral cortex but are disrupted by exposure to alcohol. Carrying her interest in brain development to a post-doctoral position in the Department of Neurology at the University of California, San Francisco, Dr. Siegenthaler began work on the novel idea that some of the important signals that instruct brain development come from a structure that sits immediately next the brain and spinal cord: the meninges. In the adult, the meninges form a protective covering around the brain, whereas during fetal development, the meninges secrete short-range signals that act on neural progenitor cells and neurons residing within the brain. Dr. Siegenthaler used a knockout mouse of the gene Foxc1, which does not form complete meninges around the outside of the cerebral cortex, to show that retinoic acid from the meninges is needed for proper neuron generation in the cerebral cortex. Her lab at the University of Colorado has continued this research on meninges-neural signaling during development as well as understanding how Foxc1 regulates meninges formation.

The idea that a non-neural structure like the meninges is so important to brain development turned Dr. Siegenthaler’s attention toward another non-brain structure that is vital in supporting brain growth and neural function: the brain vascular system. Brain blood vessels, comprised of endothelial cell tubes covered by a nearly continuous layer of vascular smooth muscle cells and pericytes, begin to enter the neural tissue very early in development. Once in the neural tissue, new blood vessels are formed from existing ones through a process called angiogenesis. Brain angiogenesis is needed for new vessel growth during fetal development and in certain instances in the adult, notably after injury. The brain vasculature has several unique features that distinguish it from blood vessels in other organs. These features include a blood-brain barrier (BBB) that protects the brain from potentially damaging blood-borne agents and immune cells, a high capillary density to support the metabolic needs of the active brain, and an unusually large population of pericytes that cover and support the brain vasculature. A major area of research in the Siegenthaler lab is to understand how these brain-specific features of the vasculature are determined during development. Currently, they are focused on 1) key endothelial signaling pathways like retinoic acid signaling, WNT signaling and the transcription factor Sox17 and 2) factors that regulate recruitment and maturation of pericytes.

Vascular instability is a frequent pathological feature of CNS disease or injury and can cause or exacerbates neuronal cell death, edema, and neuro-inflammation. Breakdown in the BBB is a common feature of vascular instability but can also be characterized by vascular dysplasia and loss of blood vessels that lead to insufficient tissue perfusion and hypoxia. The Siegenthaler lab studies some of the mechanisms underlying vascular instability in disease, specifically in ischemic stroke and viral encephalitis. These include endothelial signaling pathways that trigger loss of BBB features, including tight-junctional disorganization and pericyte loss.

Bonney, S and Siegenthaler JA (2017) “Differential Effects of Retinoic Acid Concentrations in Regulating Blood-Brain Barrier Properties.” eNEURO May 26;4(3) DOI: 10.1523/ENEURO.0378-16.2017.

Mishra, S, Choe, Y, Pleasure, SJ, Siegenthaler JA (2016) “Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGFA pathways downstream of retinoic acid from the meninges.” Developmental Biology doi: 10.1016/j.ydbio.2016.09.019.

Bonney*, S, Harrison-Uy*, S, Mishra, S, MacPherson, A, Choe, Y, Li, D, Jaminet, SC, Fruttiger, M, Pleasure, SJ and Siegenthaler, JA(2016) “Diverse functions of retinoic acid in brain vascular development.” Journal of Neuroscience 36(29):7786-801. *Co-first authors

Kelly, KK, MacPherson, A, Grewal, H, Strnad , Jones, J, Yu , J, Pierzchalski , K, Kane, M, Herson, P, Siegenthaler, JA(2016) “Col1a1+ perivascular cells in the brain are a source of retinoic acid following stroke.” BMC Neuroscience 17(49) DOI: 10.1186/s12868-016-0284-5.

Siegenthaler, JA, Choe, Y., Patterson, K., Hsieh, I., Li, D., Jaminet, S., Daneman, R., Kume, T., Huang, E. and Pleasure, S. (2013). Foxc1 is required by pericytes during fetal brain angiogenesis. Biology Open: The Company of Biologists, 2(7):647-59.

Siegenthaler, JA, Sohet, F and Daneman, R (2013) “Sealing off the CNS: cellular and molecular regulation of blood brain barriergenesis” Current Opinion in Neurobiology 23(6):1057-64.

Siegenthaler, JA, Ashique, AM, ,Zarbalis, K, Patterson, KP, Hecht, JH, Kane, MA, Folias, AE, Choe, Y, May, SR, Kume, T, Napoli, JL, Peterson, AS, Pleasure, SJ (2009) “Retinoic acid from the meninges regulates cortical neuron generation.” Cell, 139:597-609.

Zarbalis*, K, Siegenthaler*, JA, Choe, Y, May, SR, Peterson, AS, Pleasure, SJ (2007) “A novel hypomorphic Foxc1 allele with disruption of meningeal differentiation causes cortical dysplasia and skull defects.” PNAS 104:14002-14007. *Co-first authors.

Siegenthaler, JA and Pleasure, SJ (2011) “We have got you covered: how the meninges control brain development.” Current Opinion in Genetics and Development. 21(3): 249-55. *Co-first authors

All publications on PubMed:

Siegenthaler Lab
University of Colorado, Anschutz Medical Campus
RC1 North, 4th Floor 4404J MS-8313
12800 E. 19th Avenue
Aurora, CO 80045
Phone: 303-724-3123
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