Huang Laboratory

UCSF Department of Pathology

Pediatric Neuropathology and Developmental Neurobiology

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-β-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 TGFβ signaling mechanisms regulate survival, dendritic growth and synaptic plasticity of DA neurons. We use mouse genetics and molecular and cell biology to characterize how TGFβ type II receptor (TβRII) and 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.

Publications:

Berthet A, Margolis EB, Zhang J, Hsieh I, Zhang J, Hnasko TS, Ahmad J, Edwards RH, Sesaki H, Huang, E.J., Nakamura K. Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons. J Neurosci 34(43):14304-17, 2015.
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.
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-β-TAK1-depdendent Mechanisms. PLoS Biology 11(4):e1001527, 2013.
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.
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.
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.
Doxakis, E., Huang, E.J. and Davies, A.M. Homeodomain interacting protein kinase 2 (HIPK2) regulates apoptosis in developing sensory and sympathetic neurons. Curr Biol 14(19): 1761-1765, 2004.
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.

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.

Publications:

Sun S, Ling SC, Qiu J, Albuquerque CP, Zhou Y, Tokunaga S, Li H, Qiu H, Bui A, Yeo GW, Huang, E.J., Eggan K, Zhou H, Fu XD, Lagier-Tourenne C, Cleveland DW. ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nat Commun 6:6171, 2015.
Sephton CF, Tang AA, Kulkarni A, West J, Brooks M, Stubblefield JJ, Liu Y, Zhang MQ, Green CB, Huber KM, Huang, E.J., Herz J, Yu G. Activity-dependent FUS dysregulation disrupts synaptic homeostasis. Proc Natl Acad Sci U S A 111(44):E4769-78, 2014.
Qiu H*, Lee S*, Shang Y, Wang WY, Au KF, Kamiya S, Barmada SJ, Finkbeiner S, Lui H, Tang AA, Oldham MC, Wang H, Shorter J, Filiano AJ, Roberson ED, Tourtellotte WG, Chen B, Tsai LH, Huang, E.J. ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. J Clin Invest.2014 Feb 10. [Epub ahead of print][Featured in JCI Scientific Show Stopper: http://www.jci.org/posts/132]
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)
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.
Zhang, J. and Huang, E.J. Dynamic Expression of Neurotrophic Factor Receptors in Postnatal Spinal Motoneurons and Mouse Model of ALS. J Neurobiol 66, 882-895, 2006.

Our ability to examine postmortem human brains from stages as early as the second trimester to advanced aging provides a unique opportunity to investigate many important questions about human brain development. It also allows us to determine how diseases might disrupt or interfere with critical processes, such as dendrite formation and circuit formation. We have developed both independent and collaborative efforts that target the cellular and molecular mechanisms of neurological diseases, including germinal matrix hemorrhage, perinatal hypoxic ischemic injury, and neurodegenerative diseases, such as Parkinson’s disease, ALS, FTLD and Alzheimer’s disease. To further expand our scope of research, we have developed a concerted effort to systematically collect and examine brains from a wide range of age spectrum. While the complexity of human brain is daunting, we believe the resources developed through our efforts hold the keys to unlock many critical questions about human diseases, including the pathogenesis of complex neuropsychiatric diseases, such as autism and schizophrenia.

Publications:

Tate MC, Lindquist RA, Nguyen T, Sanai N, Barkovich AJ, Huang, E.J., Rowitch DH, Alvarez-Buylla A. Postnatal growth of the human pons: a morphometric and immunohistochemical analysis. J Comp Neurol 523(3):449-62, 2014.
Fancy SP, Harrington EP, Baranzini SE, Silbereis JC, Shiow LR, Yuen TJ, Huang, E.J., Lomvardas S, Rowitch DH. Parallel states of pathological Wnt signaling in neonatal brain injury and colon cancer. Nat Neurosci (4):506-12, 2014.
Nobuta, H., Ghiani, C.A., Paez, P.M., Spreuer, V., Dong, H., Korsak, R.A., Manukyan, A., Li, J., Vinters, H.V., Huang, E.J., Rowitch, D.H., Sofroniew, M.V., Campagnoni, A.T., de Vellis, J. and Waschek, J.A. STAT3-Mediated astrogliosis protects myelin development in neonatal brain injury. Ann Neurol. 72(5): 750-65, 2012.
Kwan, K.Y., Lam, M.M.S., Johnson, M.B., Dube, U., Shim, S., Rasin, M-R., Sousa, A.M.M., Fertuzinhos, S., Chen, J.G., Arellano, J.I., Chan, D.W., Pletikos, M., Vasung, L., Rowitch, D.H., Huang, E.J., Schwartz, M.L., Willemsen, R., Oostra, B.A., Rakic, P., Heffer, M., Kostovic, I., Judas, M. and Sestan, N. Species-Dependent Posttranscriptional Regulation of NOS1 by FMRP in the Developing Cerebral Cortex. Cell 149, 899Ð911, 2012.
Sanai, N., Nguyen, T., Ihrie, R.A., Mirzadeh, Z., Tsai, H.H., Wong, M., Gupta, N., Berger, M.S., Huang, E.J., Garcia-Verdugo, J.M., Rowitch, D.H. and Alvarez-Buylla, A. Corridors of Migratory Neurons in Human Brain and their Decline During Infancy. Nature 478(7369): 382-6, 2011.
Fancy, S.P.J., Harrington, E.P., Baranzini, S.E., Zhao, C., Silberesis, J.C., Otero, J.J., Huang, E.J., Nusse, R., Franklin, R.J.M. and Rowitch, D.H. Wnt inhibitor AXIN2 as regenerative medicine target in multiple sclerosis and neonatal white matter injury. Nature Neurosci 14(8): 1009-16, 2011.
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