Neuroscience Graduate Program at UCSF
Cell Biology of Midbrain Dopaminergic (DA) Neurons
Cell Biology of Midbrain Dopaminergic (DA) Neurons
How do trophic factors regulate the development and maintenance of DA neurons?
DA neurons in the substantia nigra (SN) and ventral tegmental area (VTA) control a number of important psychomotor behaviors, from motor learning to addictive behaviors. Dysfunction or degeneration in DA neurons has been implicated in several neuropsychiatric disorders, such as Parkinson’s disease and schizophrenia. Understanding the molecular mechanisms that govern the differentiation, survival, and target innervation in DA neurons will provide important insights to the pathogenesis of these debilitating diseases. Previously, we have shown that Wnt-b-catenin and sonic hedgehog (Shh)-Smo signaling mechanisms regulate the expansion of DA progenitors and differentiation of DA neurons during embryonic development. Our recent efforts focus on how TGFb signaling mechanisms regulate survival, dendritic growth and synaptic plasticity of DA neurons. We use mouse genetics and molecular and cell biology to characterize how TGFb type II receptor (TbRII) and TGFb downstream transcriptional cofactor HIPK2 affect survival, homeostasis and maintenance of DA neurons in postnatal life. Furthermore, we also use experimental paradigms of neurodegeneration to determine whether the same signaling mechanisms can be “hijacked” to promote neuronal dysfunction and degeneration in human disease conditions.
Molecular and Cellular Mechanisms of FTLD and ALS
How disease genes in FTLD and ALS contribute to the pathogenesis of neurodegeneration
Frontotemporal lobar degeneration (FTLD) is the second most common neurodegenerative disease in patients younger than 60 years old. A significant number of FTLD patients develop motor neuron degeneration with cellular and molecular signatures similar to those seen in patients with amyotrophic lateral sclerosis (ALS). To understand mechanisms that connect these two devastating diseases, we focus on genes in which mutations have been causally linked to human diseases. Specifically, our results show that FTLD gene Progranulin (PGRN) is required to suppress neuroinflammation in injury or toxin-induced neurodegenerative conditions. Loss-of-function in PGRN promotes neurodegeneration through activation of microgliosis and increases in proinflammatory cytokines. Our current effort focuses on how PGRN deficiency causes both cell autonomous and non-cell autonomous defects leading to neurodegeneration in the aging process. Finally, we are interested in characterizing the similarities and differences among three different ALS mouse models, ALS-SOD1, ALS-FUS and ALS-TDP43. Our efforts to compare and contrast these different models should provide new insights to the pathogenesis and therapeutics for both familial and sporadic ALS.
Signaling mechanisms of TGFb in the development and maturation of DA neurons
Mechanisms of HIPK2 in ER stress-induced neurodegeneration
Mouse models of Progranulin and FUS mutations in FTD and ALS
Hsin-Yi Huang, Postdoctoral Fellow
Sebum Lee, Postdoctoral Fellow
Hansen Lui, Junior Specialist
Sarah Xinwei Luo, Neuroscience Graduate Student
Haiyan Qiu, Postdoctoral Fellow
Yulei Shang, Postdoctoral Fellow
Amy Tang, Lab Manager
Leah Timbang, Junior Specialist
Jiasheng Zhang, Specialist
Wiggins, A.K., Wei, G., Doxakis, E., Wong, C., Tang, A.A., Zeng, K., Luo, E.J., Neve, R.L., Reichardt, L.F. and Huang, E.J. Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival. J Cell Biol 167 (2): 257-267, 2004.
Zhang, J., Pho, V., Bonasera, S.J., Holzmann, J., Helmuth, J., Tang, A.A., Janak, P.H., Tecott, L.H. and Huang, E.J. Essential function of HIPK2 in TGFb-dependent survival of midbrain dopamine neurons. Nature Neuroscience 10:77-86, 2007.
Tang, M., Villaescusa, J.C., Luo, S.X., Guitarte, C., Lei, S., Miyamoto, Y., Maketo, M.M., Arenas, E. and Huang, E.J. Interactions of Wnt/b-catenin signaling and sonic hedgehog regulate the neurogenesis of midbrain dopamine neurons. J Neurosci 30: 9280-9, 2010.
Tang, M., Miyamoto, Y. and Huang, E.J. Multiple roles of b-catenin in controlling the neurogenic niche for midbrain dopamine neurons. Development 136: 2027-2038, 2009.
Reyes, N.A., Fisher, J.K., Austgen, K., VandenBerg, S., Huang, E.J. and Oakes, S.A. Blocking the mitochondrial apoptotic pathway protects against neurodegeneration. J Clin Invest 120: 3673-9, 2010.
Huang, E.J., Zhang, J., Geser, F., Trojanowski, J.Q., Strober, J.B., Dickson, D.W., Brown, R.H., Jr., Shapiro, B.E. and Lomen-Hoerth, C. Extensive FUS-immunoreactive Pathology in Juvenile amyotrophic lateral sclerosis with Basophilic Inclusions. Brain Pathology 20: 1069-76, 2010.
Chalazonitis, A., Tang, A.A., Shang, Y., Pham, T.D., Hsieh, I., Setlik, W., Gershon, M.D. and Huang, E.J. Homeodomain Interacting Protein Kinase 2 Regulates Postnatal Development of Enteric Dopamine Neurons and Glia via BMP Signaling. J Neurosci 31(39): 13746-57, 2011.
Martens, L.H., Zhang, J., Zhou, P., Kamiya, S., Sun, B., Min, S.-W., Zhang, Y., Diaz-Ramirez, G., Gan, L., Huang, E.J.* and Farese, Jr., R.V.* Progranulin deficiency promotes microglial activation, proinflammtory cytokine production, and aggravated neuronal loss in toxin-induced neurodegeneration. J Clin Invest 122(11): 3955-9, 2012 (*co-corresponding authors)
Shang, Y., Doan, C., Arnold, T.D., Lee, S., Tang, A.A., Reichardt, L.F. and Huang, E.J. Transcriptional Corepressors HIPK1 and HIPK2 Control Angiogenesis via TGF-b-TAK1-depdendent Mechanisms. PLoS Biology 11(4):e1001527, 2013.
Tang, M., Luo, S.X., Tang, V. and Huang, E.J. Temporal and spatial requirements of smoothened in ventral midbrain neuronal development. Neural Dev 8(1): 8, 2013.
Eric J. Huang, M.D./Ph.D.
415-476-1946 or 415-476-8525
Department of Pathology
UCSF MC 0502
505 Parnassus Ave
San Francisco, CA 94143-0502