Jeffrey L. Neul, M.D., Ph.D.
Associate Professor of Molecular and Human Genetics
Associate Professor, Departments of Pediatrics - Section of Neurology, Molecular Physiology and Biophysics, and Neuroscience; Programs in Developmental Biology and Translational Biology and Molecular Medicine
Medical Co-Director, Blue Bird Circle Rett Center
Anthony and Cynthia Petrello Scholar, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
Ph.D., University of Chicago, 1998
M.D., University of Chicago, 2000
Pediatrics Intern, Baylor College of Medicine, 2001
Child Neurology Fellow, Baylor College of Medicine, 2005
Rett Syndrome is an X-linked neurodevelopmental disease that primarily affects girls and is caused in the majority of cased by mutations in Methyl-CpG-binding Protein 2 (MECP2). This disease is characterized by loss of hand skills, loss of spoken language, and development of repetitive hand movements. In addition to these features, affected people also have a variety of clinical features including movement problems such as dystonia and tremor, growth failure, and anxiety. Notably, autonomic abnormalities such as breathing irregularities, heart rhythm abnormalities, and vasomotor disturbances are extremely common in this disease and these abnormalities are thought to underlie the sudden unexpected death observed in a fraction of affected people. Most boys with mutations in MECP2 are severely affected with congenital encephalopathy and marked autonomic abnormalities. These autonomic abnormalities lead to death within the first years of life.
We are interested in using animal models and molecular techniques to understand the mechanisms that cause some of the specific clinical features found in Rett Syndrome. Specifically, we are interested in the neuroanatomic and molecular basis of autonomic abnormalities. We determined that a mouse model reproduces many of the autonomic abnormalities observed in people with Rett syndrome, including breathing problems and abnormal heart rhythm. Male mice that lack all MeCP2 function also have a markedly shortened lifespan and we believe that these autonomic abnormalities are the cause. To determine the neuroanatomic basis of the autonomic abnormalities and shortened lifespan, we utilize tissue conditional knock-out techniques to remove MeCP2 from particular anatomic regions and determine the specific phenotypic abnormalities that results. From this approach we discovered that MeCP2 plays a role within aminergic neurons (dopamine, norepinephrine, serotonin) to control the expression of the synthetic enzymes that control the production of these neurotransmitters and that disrupting MeCP2 within these neurons results in specific behavioral abnormalities. We subsequently have determined that removing MeCP2 from the medulla and spinal cord results in premature death and autonomic abnormalities. We are now using molecular and cellular techniques to determine which neural circuits underlie these abnormalities. We hope to use this information to develop therapeutic strategies to treat these phenotypes in the animal model and eventually translate this knowledge in to treatment approaches to affected people.
- McCauley MD, Wang T, Mike E, Herrera J, Beavers DL, Huang TW, Ward CS, Skinner S, Percy AK, Glaze DG, Wehrens XH, Neul JL (2011). Pathogenesis of lethal cardiac arrhythmias in Mecp2 mutant mice: implication for therapy in Rett syndrome. Sci. Transl. Med. 3(113): 113ra125. PubMed PMID: 22174313
- Ward CS, Arvide EM, Huang TW, Yoo J, Noebels JL, Neul JL (2011). MeCP2 is critical within HoxB1-derived tissues of mice for normal lifespan. J. Neurosci. 31(28): 10359-70. PubMed PMID: 21753013
- Samaco RC, Neul JL (2011). Complexities of Rett syndrome and MeCP2. J. Neurosci. 31(22): 7951-9. PubMed PMID: 21632916
- Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, Leonard H, Bailey ME, Schanen NC, Zappella M, Renieri A, Huppke P, Percy AK; RettSearch Consortium (2010). Rett syndrome: revised diagnostic criteria and nomenclature. Ann. Neurol. 68(6): 944-50. PubMed PMID: 21154482
- Percy AK, Neul JL, Glaze DG, Motil KJ, Skinner SA, Khwaja O, Lee HS, Lane JB, Barrish JO, Annese F, McNair L, Graham J, Barnes K (2010). Rett syndrome diagnostic criteria: lessons from the Natural History Study. Ann. Neurol. 68(6): 951-5. PubMed PMID: 21104896
- 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(7321): 263-9. PubMed PMID: 21068835
- Samaco RC, Mandel-Brehm C, Chao HT, Ward CS, Fyffe-Maricich SL, Ren J, Hyland K, Thaller C, Maricich SM, Humphreys P, Greer JJ, Percy A, Glaze DG, Zoghbi HY, Neul JL (2009). Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities. Proc. Natl. Acad. Sci. U S A 106(51): 21966-71. PubMed PMID: 20007372
- 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. PubMed PMID: 18817733
- Neul JL, Fang P, Barrish J, Lane J, Caeg EB, Smith EO, Zoghbi H, Percy A, Glaze DG. (2008). Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology 70(16): 1313-21. PubMed PMID: 18337588
- Samaco R, Fryer J, Fyffe S, Chao HT, Zoghbi H, Neul JL (2008) A partial loss of function allele of Methyl-CpG-Binding Protein 2 predicts a human neurodevelopmental syndrome. Hum. Mol. Genet. 17(12): 1718-27. PubMed PMID: 18321864
Jeffrey L. Neul, M.D., Ph.D.
Jan and Dan Duncan Neurological Research Institute
1250 Moursund St., Suite 1250
Houston, TX, 77030, U.S.A.