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Siegenthaler Lab

​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.

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 throughout a lifetime: 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 that protects the brain from potentially damaging blood-borne agents and 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 interest of the Siegenthaler lab is to understand how these brain-specific features of the vasculature are determined during development. Specifically, her lab is looking at the unique molecular signaling within endothelial cells and pericytes as well as the nature of brain-derived signals that stimulate angiogenesis within the brain. Some of the angiogenic pathways of interest include vascular endothelial growth factor, Wnt, retinoic acid and transforming growth factor-β.

Another major area of interest of the lab is determining how pericytes that cover the brain vasculature communicate with endothelial cells to regulate vascular stability. Foxc1, critical for development of the meninges, is also needed for the ability of pericytes to regulate endothelial cell proliferation. Using genetic mouse mutants of Foxc1, the Siegenthaler lab is looking for pericyte-derived signals that are transcriptionally regulated by Foxc1.

Amber Macpherson, BS, Professional Research Assistant
SwatiMishra (108) 2013 (2) - resized to 3rd.jpg Swati Mishra, BS, Graduate Student Assistant
TanakaKathleen (088) 2013 (2) - resized to 3rd.jpg Kathleen Tanaka, PhD, Research Associate

Harrison-Uy S, Siegenthaler JA, Faedo A, Rubenstein JL, Pleasure SJ (2013) CoupTFI interacts with retinoic acid signaling during cortical development.  PLoS One. (3):e58219.

Siegenthaler JA, Xu L, Basile AS, Tang-Liu DD, Giacomini KM (2013) Gene expression profiling of transporters in the solute carrier and ATP-binding cassette superfamilies in human eye substructures.” Molecular Pharmacology 10(2):650-63.

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, May 20;2(7):647-59.

Siegenthaler JA and Miller MW (2005) Ethanol disrupts cell cycle regulation in developing rat cortex interaction with transforming growth factor beta1.  Journal of Neurochemistry, 95: 902-912.

Siegenthaler JA, Pleasure SJ (2012) A cascade of morphogenic signaling initiated by the meninges controls corpus callosum formation. Neuron 23:698-712.

Zarbalis K, Choe Y, Siegenthaler JA, Orosco LA, Pleasure SJ (2012) Meningeal defects alter the tangential migration of cortical interneurons in Foxc1hith/hith mice. Neural Development, Jan 17;7:2.

Munji R, Choe Y, Li G, Siegenthaler JA, Pleasure SJ (2011) Wnt signaling regulates neuronal differentiation of cortical intermediate progenitors.  Journal of Neuroscience 31(5:1676-87.

Chen L, Takizawa M, Chen E, Schlessinger A, Siegenthaler JA, Choi JH, Sali A, Kubo M, Nakamura S, Iwamoto Y, Iwasaki N, Giacomini KM (2010) Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function.  Journal of Pharmacology and Experimental Therapeutics 335(1):42-50.

Hecht JH, Siegenthaler JA, Patterson KP, Pleasure SJ (2010) Primary cellular meningeal defects cause neocortical dysplasia and dyslamination.  Annals of Neurology 68(4):454-64.

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.

Siegenthaler* JA, Tremper-Wells* B, and Miller MW (2008) Foxg1 haplo-insufficiency reduces the population of cortical intermediate progenitor cells: effect of increased p21 expression. Cerebral Cortex, 8:1865-1875.  *Co-first authors

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 Miller MW (2007) Generation of Cajal-Retzius neurons in mouse forebrain is regulated by transforming growth factor-beta-Fox signaling pathways. Developmental Biology, 313: 35-46.

Siegenthaler JA and Miller MW (2005) TGF beta1 promotes cell cycle exit through the CKI p21 in the developing cerebral cortex.  Journal of Neuroscience, 25(38):8627-8636.

Siegenthaler Lab
University of Colorado Denver
RC1 North, 7th Floor
12800 E. 19th Avenue
Aurora, CO 80045
Phone: 303-724-3123