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Molecular and Human Genetics

Houston, Texas

Department of Molecular and Human Genetics
Department of Molecular and Human Genetics
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Huda Y. Zoghbi, M.D.

Huda Y. Zoghbi, M.D.

Professor, Department of Molecular and Human Genetics

Other Positions

Professor, Departments of Pediatrics, Neurology, and Neuroscience; Programs in Cell & Molecular Biology, Developmental Biology, and Translational Biology & Molecular Medicine
 Investigator, Howard Hughes Medical Institute

Education

M.D., American University of Beirut/Meharry Medical College, 1979
Postdoc, Baylor College of Medicine, 1985

Research Interests

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 (ATXN1) with an expanded glutamine tract accumulates in neurons of patients and mouse models and redistributes components of the protein folding and degradation machinery. Genetic studies in Drosophila and mice showed that high levels of wild-type (WT) ATXN1, produce effects similar to mutant ATXN1. This suggested that ATXN1 exists in alternate conformations, one of which is more favored by the expanded glutamine tract and resists degradation and that enhanced activity/interactions of ATXN1 contribute to SCA1 pathogenesis. Together with our collaborators, we found that ATXN1 interacts with several proteins many of which are transcriptional regulators such as Gfi-1, RORα, and Capicua, and somehow interferes with their function in vivo (Tsuda, 2005; Lam, 2006; Sierra, 2006). Importantly, we found that mutant ATXN1 must be in its large native complexes to cause neurodegeneration and that it has enhanced interactions with RBM17 (causing gain-of-function) at the expense of interactions with CIC (partial loss-of-function) (Lam, 2007; Lim, 2008). Moreover, we discovered that the ATXN1 paralog, ATXN1-Like, also interacts with CIC, and that increasing ATXN1-Like levels suppress SCA1 phenotypes in the Sca1154Q/2Q knock-in mouse models by displacing mutant ATXN1 from its large native complex allowing its sequestration away from its native interactions into nuclear inclusions (Bowman, 2007). Given the prominent role of ATXN1 in transcriptional regulation, we explored lithium therapy in the SCA1 knock-in mice and found that lithium therapy suppresses many of the SCA1 phenotypes including some histopathological and molecular changes. Our next phase of research is focusing on exploring the interactions of the proteins involved in SCA6 and SCA7 to see if some of the principles we learned about SCA1 apply to these other polyglutamine disorders. We will also continue our studies of ATXN1, its interactions, modifiers of its toxicity and will begin the design of studies to test if lithium will have any benefit in human patients.

We discovered that mutations in the X-linked gene 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).

MeCP2

MeCP2 localizes to heterochromatic domains in mature neurons.

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 beginning to reveal mechanism of pathogenesis. Neurophysiological studies revealed that MeCP2 levels are critical for regulating excitatory synapse numbers. Gene expression studies using both MeCP2 null and duplication mice identified many MeCP2 targets, and illustrated that the duplication causes disease by a gain-of-function mechanism. These studies surprisingly revealed that MeCP2 is also an activator of gene expression.

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 globlet/paneth differentiation. The identification of TCF4 as a binding partner of Math1 provided insight about how bHLH proteins might partner to specify different neurons (Flora, 2007).

Selected Publications

  1. 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(6): 947-58. [Pub Med]
  2. 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(7188): 713-8. [Pub Med]
  3. Chahrour M, Jung SY, Shaw C, Zhou X, Wong STC, Qin J, Zoghbi HY (2008). MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription. Science 320(5880): 1224-9. [Pub Med]
  4. Flora A, Garcia JJ, Thaller C, Zoghbi HY (2007). The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors. Proc. Natl. Acad. Sci. USA 104(39): 15382-7. [Pub Med]
  5. Bowman, AB, Lam YC, Jafar-Nejad P, Chen H-K, Richman R, Samaco RC, Fryer JD, Kahle JJ, Orr HT, Zoghbi HY (2007). Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. Nat. Genet. 39(3): 373-9. [Pub Med]
  6. Lam YC, Bowman AB, Jafar-Nejad, Lim J, Richman R, Fryer JD, Hyun ED, Duvick LA, Orr HT, Botas J, Zoghbi HY (2006). Mutant ATAXIN-1 interacts with the transcriptional repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127(7): 1335-47. [Pub Med]
  7. Wang VY, Rose MF, Zoghbi HY (2005). Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron 48(1): 31-43. [Pub Med]
  8. Shahbazian M, Young YI, Yuva-Paylor LA, Antalffy BA, Spencer CM, Noebels JL, Armstrong DL, Paylor R, Zoghbi HY (2002). Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35(2): 243-54. [Pub Med]
  9. Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DL, Noebels JL, David Sweatt J, Zoghbi HY (2004). Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum. Mol. Genet. 13(21): 2679-89. [Pub Med]
  10. Amir R, Van den Veyver IB, Wan M, Tran C, Francke U, Zoghbi HY (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23(2): 185-8. [Pub Med]

More Publications (PubMed)

Awards and Honors

2009: International Rett Syndrome Foundation's Circle of Angels Research Award
2009: Vilcek Prize for Biomedical Research
2008: Honorary Doctorate of Science, Meharry Medical School, TN; Texas Women's Hall of Fame Award Texas Governor's Commission for Women Abilene, TX
2007: Robert J. and Claire Pasarow Foundation Award in Neuropsychiatry, Los Angeles , CA; Honorary Doctorate of Science, Middlebury College, Middlebury, VT
2006: Bristol-Myers Squibb Neuroscience Distinguished Achievement Award
2004: Elected, National Academy of Sciences; Neuronal Plasticity Prize, IPSEN Foundation, Lisbon , Portugal; Marta Philipson Award in Pediatrics, Philipson Foundation for Research, Stockholm, Sweden
2002: Raymond D. Adams Award, American Neurological Association; Elected Fellow, AAAS
2001: Bernard Sachs Award, Child Neurology Society
2000: Elected to the Institute of Medicine , National Academy of Sciences
1998: Sidney Carter Award (American Academy of Neurology); Soriano Award, The American Neurological Association; Javits Award, NINDS Council, National Institutes of Health
1996: E. Mead Johnson Award, Society of Pediatric Research
1995: Kilby Award for Extraordinary Contributions to Society

Contact Information

Huda Y. Zoghbi, M.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza, MS BCM225
Houston, TX, 77030, U.S.A.

Phone: 713-798-6558
Fax: 713-798-8728
E-mail:

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