Development of the brain is extraordinarily complex and requires the precise coordination of both cellular and molecular processes. The establishment of dorsal-ventral and rostral-caudal axes is an essential step in early brain formation. Disturbances in this process can result in Mental retardation and brain malformations. In fact, holoprosencephaly (HPE), a severe brain anomaly, can arise from abnormalities in genes regulating dorsal-ventral patterning. Haploinsufficiency for Sonic Hedgehog (Shh), a secreted factor which induces ventral identity of the brain, causes HPE in humans. In addition, overexpression of bone morphogenetic protein 5 (BMP5), a dorsal brain inducer, also results in HPE. These data indicate that HPE arises from aberrant dorsal-ventral specification. This proposal seeks to examine the mechanisms that determine dorsal- ventral axis formation in the, vertebrate forebrain and their relationship to the pathogenesis of human brain malformations. Since loss ot expression of Shh and ectopic expression of BMP5 both result in HPE, we hypothesize that mutations affecting other genes in these pathways will also disrupt normal patterning and lead to HPE. We will test this hypothesis in two ways. First, the mechanisms of BMP5 action in the forebrain will be examined by studying the function of BMP receptors (BMPRs) in the chick embryo, an established model of brain development. Constitutively active and dominant negative BMPR constructs will be expressed in the chick brain and the resulting morphologic, cellular, and genetic consequences will be analyzed. Second, since mutations in Shh are detected in only a fraction of HPE cases, mutation screening of several genes in the Shh and BMP pathways in individuals with HPE will be conducted. This proposal describes a five-year training program in which the applicant will acquire the skills and experience required of an independent physician scientist. The primary focus throughout the grant period will be laboratory benchwork, complemented by coursework, journal clubs, and limited clinical responsibilities relevant to the project. The expertise of the mentors will provide broad and in-depth training in two areas: an animal experimental model of development, and analysis of human genes. The proposed studies will enable the candidate to transition into an independent investigator capable of integrating mutation analysis, functional developmental studies, and clinical diagnosis in future studies of the molecular basis of development and human genetic diseases.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD001218-04
Application #
6387348
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Oster-Granite, Mary Lou
Project Start
1998-07-07
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
4
Fiscal Year
2001
Total Cost
$86,940
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Knepper, Jessica L; James, Alison C; Ming, Jeffrey E (2006) TGIF, a gene associated with human brain defects, regulates neuronal development. Dev Dyn 235:1482-90
Ming, Jeffrey E; Russell, Karen L; McDonald-McGinn, Donna M et al. (2005) Autoimmune disorders in Kabuki syndrome. Am J Med Genet A 132A:260-2
Schell-Apacik, Can; Rivero, Mariel; Knepper, Jessica L et al. (2003) SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. Hum Genet 113:170-7
Ming, Jeffrey E; Russell, Karen L; Bason, Lynn et al. (2003) Coloboma and other ophthalmologic anomalies in Kabuki syndrome: distinction from charge association. Am J Med Genet A 123A:249-52
Roessler, Erich; Du, Yang-Zhu; Mullor, Jose L et al. (2003) Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci U S A 100:13424-9
Ming, J E; Elkan, M; Tang, K et al. (2002) Type I bone morphogenetic protein receptors are expressed on cerebellar granular neurons and a constitutively active form of the type IA receptor induces cerebellar abnormalities. Neuroscience 114:849-57
Ming, Jeffrey E; Muenke, Maximilian (2002) Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet 71:1017-32
Orioli, Ieda M; Vieira, Alexandre R; Castilla, Eduardo E et al. (2002) Mutational analysis of the Sonic Hedgehog gene in 220 newborns with oral clefts in a South American (ECLAMC) population. Am J Med Genet 108:12-5
Ming, Jeffrey E; Kaupas, Michelle E; Roessler, Erich et al. (2002) Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet 110:297-301
Ion, Andra; Tartaglia, Marco; Song, Xiaoling et al. (2002) Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome. Hum Genet 111:421-7

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