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

M.D., American University of Beirut/Meharry Medical College, 1979
Postdoctoral Training, 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 (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. Genetic studies in Drosophila and mice showed that high levels of wild-type (WT) Atx-1, produce effects similar to mutant Atx-1 (Fernandez, 2000). This suggested to us that Atx-1 exists in alternate conformations, one of which is more favored by the expanded glutamine tract and resists degradation that enhanced activity/interactions of Atx-1 contribute to SCA1 pathogenesis. We searched for proteins that interact with Atx-1 in vivo. Together with our collaborators, we found that Atx-1 interacts with several proteins many of which are transcriptional regulators such as Gfi-1, RORa, and Capicua, and somehow interferes with their function in vivo (Tsuda, 2005; Lam, 2006; Sierra, 2006). Importantly, we found that mutant Atx-1 must be in its large native complex to cause neurodegeneration (Lam, 2007). Moreover, we discovered that the Atx-1 paralog, Atx-1-Like, also interacts with CIC, and that increasing Atx1-Like levels suppress SCA1 phenotypes in the Sca1^154Q/2Q knock-in mouse models by displacing mutant Atx-1 from its large native complex allowing its sequestration away from its native interactions into nuclear inclusions (Bowman, 2007). Given the prominent role of Atx-1 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 Atx1, 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 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. In parallel studies using a phenotype-driven approach, we sought the identification of molecules that might contribute to the anxiety phenotype in RTT mouse models and found that corticotropin-releasing hormone is elevated in RTT mice and that is a transcriptional target of MeCP2. We are now exploring the contribution of Crh to RTT phenotypes and whether manipulating the Crh signaling pathway would modulate such phenotypes.

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 (Shroyer, 2005). A conditional allele is allowing us to analyze Math1's postnatal function in the proprioceptive and auditory pathways and in CNS control of breathing.

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SELECTED PUBLICATIONS:
1. 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: 373-379.

2. 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: 1335-1347.

3. McGill B, Bundle SF, Yaylaoglu, MB, Carson JP, Thaller C, Zoghbi HY (2005). Enhanced anxiety and stress in a mouse model of Rett syndrome are linked to the regulation of Crh by MeCP2. PNAS 103: 18267-18272.

4. Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF, Venken KJT, Botas J, Orr HT, Bellen HJ, Zoghbi HY (2005). The AXH domain of ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/senseless proteins. Cell 122: 633-644.

5. 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: 31-43.

6. Shroyer NF, Wallis D, Venken KJT, Bellen HJ, Zoghbi HY (2005). Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes Dev. 19: 2412-2417.

7. Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH, Aitken A, Skoulakis EMC, Orr HT, Botas J, Zoghbi HY (2003). Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113: 1-12.

8. Shahbazian MD, 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: 1-20.

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: 2679-2689.

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: 185-188.

For more publications, see listing on Pub Med.

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CONTACT INFORMATION:
Huda Y. Zoghbi, M.D.
Department of Pediatrics
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030, U.S.A.

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

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