Professor, Baylor College of Medicine
Investigator, Howard Hughes Medical Institute
Director, Jan and Dan Duncan Neurological Research Institute
B.S., American University of Beirut, Lebanon, 1976
M.D., Meharry Medical School, Nashville, TN, 1979
Postdoc, Baylor College of Medicine, Houston, TX, 1985-88
Neural development, neurodegenerative and neurodevelopmental disorders
My laboratory uses genetic behavioral and cell biological approaches to explore the pathogenesis of polyglutamine neurodegenerative diseases and Rett syndrome, and to study genes essential for normal neurodevelopment.
Several dominantly inherited spinocerebellar ataxias (SCAs) are caused by expansion of a CAG repeat that encodes glutamine. We discovered that ataxin-1 (Atx-1) with an expanded glutamine tract accumulates in neurons of patients and mouse models and redistributes components of the protein folding and degradation machinery. We hypothesized that mutant ataxin-1 misfolds and resists degradation, and showed that ataxin-1 toxicity is suppressed by chaperone overexpression (Cummings 1999, 2001). Genetic studies in Drosophila and mice showed that high levels of wild-type (WT) Atx-1, produce effects similar to mutant Atx-1 (Fernández-Fúnez, 2000). This suggested to us that Atx-1 exists in alternate conformations, one of which is more favored by the expanded glutamine tract, and that enhanced activity/interactions of Atx-1 contribute to SCA1 pathogenesis. To this end, we found that WT and mutant Atx-1 interact with proteins such as 14-3-3 and Gfi-1, through its C-terminal region and that the polyglutamine tract simply modulates the interaction or its consequences (Chen, 2003; Tsuda, 2005). We are now exploring additional Atx-1 interactions and testing whether enhanced or altered interactions/activity of the host protein plays a role in other polyglutamine disorders such as SCA7 and SCA6.
We discovered that mutations in the X-linked encoding methyl CpG-binding protein2 (MECP2) cause Rett syndrome (Amir, 1999). MECP2 mutations also cause autism, mild or severe retardation, and even psychosis. We generated mice carrying a truncating mutation and found that they reproduce most of the features of Rett syndrome (Shahbazian, 2002). We also generated mice that overexpress MECP2 at twice the normal levels and found that they develop a progressive neurodevelopmental disorder (Collins, 2004). This led us to propose that duplications of MECP2 might lead to postnatal neurologic disorders, which is proving to be the case. Studies of both mouse models are ongoing to reveal mechanism of pathogenesis in Rett and potential MECP2 targets.
My lab identified Math1, the mouse homolog of Drosophila atonal, and showed that Math1 is essential for genesis of cerebellar granule neurons, DI spinal cord interneurons, inner ear hair cells, (Bermingham, 1999), and secretory cells (paneth, goblet, and enteroendocrine) of the gut. Recently, we discovered that Math1 redefines the rhombic lip and its derivations and that loss of Math1 leads to loss of large, deep cerebellar neurons (Wang, 2005). In collaboration with Hugo Bellen, we found that in mice, Gfi-1 is a downstream target of Math1 (just like senseless is downstream of atonal) and is critical for enteroendocrine vs goblet/paneth differentiation (Shroyer, 2005). A conditional allele is allowing us to analyze Math1‘s postnatal function in the proprioceptive pathway and in CNS control of breathing.
Fyffe SL, Neul JL, Samaco RC, Chao HT, Ben-Shachar S, Moretti P, McGill BE, Goulding EH, Sullivan E, Tecott LH, Zoghbi HY (2008) Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron 59:947-958.
Lim J, Crespo-Barreto J, Jafar-Nejad P, Bowman AB, Richman R, Hill DE, Orr HT, Zoghbi HY (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452:713-718.
Ramocki MB, Zoghbi HY (2008) Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455:912-918.
Flora A, Klisch TJ, Schuster G, Zoghbi HY (2009) Deletion of Atoh1 disrupts Sonic Hedgehog signaling in the developing cerebellum and prevents medulloblastoma. Science 326:1424-1427.
Maricich SM, Wellnitz SA, Nelson AM, Lesniak DR, Gerling GJ, Lumpkin EA, Zoghbi HY (2009) Merkel cells are essential for light-touch responses. Science 324:1580-1582.
Rose MF, Ren J, Ahmad KA, Chao HT, Klisch TJ, Flora A, Greer JJ, Zoghbi HY (2009) Math1 is essential for the development of hindbrain neurons critical for perinatal breathing. Neuron 64:341-354.
Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, Neul JL, Gong S, Lu HC, Heintz N, Ekker M, Rubenstein JL, Noebels JL, Rosenmund C, Zoghbi HY (2010) Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468:263-269.
Fryer JD, Yu P, Kang H, Mandel-Brehm C, Carter AN, Crespo-Barreto J, Gao Y, Flora A, Shaw C, Orr HT, Zoghbi HY (2011) Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua. Science 334:690-693.
Lee Y, Fryer JD, Kang H, Crespo-Barreto J, Bowman AB, Gao Y, Kahle JJ, Hong JS, Kheradmand F, Orr HT, Finegold MJ, Zoghbi HY (2011) ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization. Developmental Cell 21:746-757.
McGraw CM, Samaco RC, Zoghbi HY (2011) Adult neural function requires MeCP2. Science 333:186.
Huang WH, Tupal S, Huang TW, Ward CS, Neul JL, Klisch TJ, Gray PA, Zoghbi HY (2012) Atoh1 governs the migration of postmitotic neurons that shape respiratory effectiveness at birth and chemoresponsiveness in adulthood. Neuron 75:799-809.
Huda Y. Zoghbi, M.D.
Department of Pediatrics
Baylor College of Medicine
1250 Moursund St. – NRI, Suite N1350.12
Houston, Texas 77030, U.S.A.
Tel: (713) 798-6558
Fax: (713) 798-8728