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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 globlet/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.
Selected Publications
Bermingham NA, Hassan BA, Price SD, Vollrath MA, Ben-Arie N, Eatock RA, Bellen HJ, Lysakowski A, Zoghbi
HY (1999) Math1: an essential gene for the generation of inner ear hair cells. Science 284:1837-1841.
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused
by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics 23:185-188.
Fernández-Fúnez P, Niño-Rosales ML, de Gouyon B, She W-C, Luchack JM, Martinez P, Turiegano E,
Benito J, Capovilla M, Skinner PJ, McCall A, Canal I, Orr HT, Zoghbi HY, Botas J (2000) Identification
of genes that modify ataxin-1-induced neurodegeneration. Nature 408:101-106.
Shahbazian MD, Young JI, Yuva-Paylor LA, Spencer CM, Antalffy BA, 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 35:243-254.
Chen HK, Fernández-Fúnez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH, Aitken A, Skoulakis EM,
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 113:457-468.
Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DL, Noebels JL, Sweatt JD, Zoghbi HY (2004)
Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Human Molecular Genetics
13:2679-2689.
Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF, Venken KJ, 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.
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.
Shroyer NF, Wallis D, Venken KJ, Bellen HJ, Zoghbi HY (2005) Gfi1 functions downstream of Math1 to
control intestinal secretory cell subtype allocation and differentiation. Genes and Development 19:2412-2417.
Contact Information
- Huda Y. Zoghbi, M.D.
- Howard Hughes Medical Institute
- Baylor College of Medicine
- One Baylor Plaza T807
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-6558
- Fax: (713) 798-8728
- E-mail: hzoghbi@bcm.tmc.edu
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