Positions

Professor
Molecular and Human Genetics
Baylor College of Medicine
Director
Jan and Dan Duncan Neurological Research Institute
Texas Children’s Hospital
Investigator
Howard Hughes Medical Institute
Professor
Pediatrics - Neurology and Developmental Neuroscience
Baylor College of Medicine
Professor
Neuroscience
Baylor College of Medicine
Professor
Program in Developmental Biology
Baylor College of Medicine
Professor
Program in Integrative Molecular and Biomedical Sciences
Baylor College of Medicine
Professor
Program in Translational Biology & Molecular Medicine
Baylor College of Medicine
Ralph D. Feigin, M.D. Endowed Chair
Baylor College of Medicine
Houston, Texas, United States

Education

BS from American University Of Beirut
MD from Meharry Medical College
Post-Doctoral Fellowship at Baylor College Of Medicine

Certifications

General Pediatrics
American Board of Pediatrics

Honors & Awards

Honorary Doctorate of Science
March of Dimes Prize in Developmental Biology
Sckolnick Prize
The Pearl Meister Greengard Prize
Dickson Prize in Medicine
Gruber Prize in Neuroscience
International Rett Syndrome Foundation's Circle of Angels Research Award
Vilcek Prize for Biomedical Research
National Academy of Sciences
Elected
Institute of Medicine, National Academy of Sciences
Elected
Texas Women's Hall of Fame Award
Texas Governor's Commission for Women
Bernard Sachs Award
Child Neurology Society
Sidney Carter Award
American Academy of Neurology
Soriano Award
The American Neurological Association
Javits Award
NINDS Council, National Institutes of Health
E. Mead Johnson Award
Society of Pediatric Research
Kilby Award for Extraordinary Contributions to Society
Bristol-Myers Squibb Neuroscience Distinguished Achievement Award
Marion Spencer Fay Award
Drexel University College of Medicine
Robert J. and Claire Pasarow Foundation Award in Neuropsychiatry
Neuronal Plasticity Prize
IPSEN Foundation
Marta Philipson Award in Pediatrics
Philipson Foundation for Research
Honorary Doctorate of Science
Meharry Medical School
Honorary Doctorate of Science
Middlebury College

Professional Interests

  • Molecular basis of neurodegenerative and neurodevelopmental disorders
  • Nervous system development

Professional Statement

My laboratory’s research is rooted in my early clinical encounters with patients suffering rare and enigmatic disorders. One memorable patient suffered Rett Syndrome; another was part of a family that suffered a neurodegenerative disease that struck each successive generation at younger ages. (We co-discovered the gene for spinocerebellar ataxia type 1 (SCA1) in 1993 with Dr. Harry Orr at the University of Minnesota.) Our investigations into the pathogenesis of these two diseases have influenced our understanding of basic neurobiology. Conversely, our foray into fundamental neurodevelopmental processes governed by Atonal homolog 1 (also known as Math1) has had unexpected ramifications for our understanding of (and potential therapies for) several diseases, from deafness to medulloblastoma.

Polyglutamine Pathogenesis and Neurodegeneration. Genetic studies in mice and fruit flies have yielded tremendous insights into SCA1 pathogenesis. In collaboration with Juan Botas (Baylor College of Medicine), we found that high levels of even wild-type Ataxin-1 can be toxic to neurons: Drosophila and mice overexpressing wild-type Ataxin-1 develop a mild version of the SCA1 phenotype. This led us to propose that the polyglutamine tract stabilizes Ataxin-1 increasing its levels and interactions and causing toxicity due to its enhanced function. Consistent with this we recently discovered that a 30-50% increase in wild-type Ataxin-1 (due to haploinsufficiency of its negative regulator, Pum1) causes cerebellar degeneration and ataxia in mice. Thus, to reduce the toxicity of Ataxin-1 and develop therapeutics for SCA1 we have embarked on cross-species genetic screens to find modulators of Ataxin-1 levels. We have also adapted a similar strategy to find modulators of other disease driving proteins like alpha-synuclein and tau.

Math1 and Neurodevelopment. We identified the mouse homolog of the Drosophila gene atonal, which controls the development and function of the fly's chordotonal organs. Math1 null mice lack cerebellar granule neurons, pontine neurons, hair cells in the vestibular and auditory systems, the D1 interneurons of the spinocerebellar tracts, and Merkel cells. This single gene controls the genesis and/or differentiation of multiple components of the conscious and unconscious proprioceptive pathway and the neurons critical for interoception, neonatal breathing and chemosensitivity. We identified Math1’s transcriptional targets and revealed its critical role in regulating proliferation and differentiation of granule neuron precursors and how this regulation might go awry in sonic hedgehog-induced medulloblastoma. We are currently focused on identifying the specific roles of certain Math1-dependent neurons in the hindbrain.

Rett Syndrome. Rett syndrome is caused by mutations in the X-linked methyl-CpG–binding protein 2 (MECP2). MeCP2 is expressed in mature neurons, and the number of MeCP2-positive cortical neurons increases postnatally as the brain matures. Our mouse model studies led to the definition of clinical phenotypes not previously appreciated in MeCP2 disorders and revealed that neurons are quite sensitive to having just slightly too much or too little MeCP2. Most surprising was the discovery that deletion of MeCP2 in adult animals reproduces all the phenotypes of animals that lack the protein throughout life. These findings suggest that MeCP2 performs a maintenance function in the brain.

We also discovered that the MeCP2 C-terminus is homologous to the HMGA family of proteins and that disruption of an AT-hook-like domain impairs MeCP2’s ability to maintain chromatin structure in neurons and that MeCP2 binds to non-CG methyl sequences providing some clues about the role of such marks in Rett pathogenesis.

Selected Publications