In the United States, abnormal craniofacial development represents a third of all birth defects. Craniofacial development depends mainly on a population of ?stem cells?, the cranial neural crest (CNC) cells. These cells originate from the lateral sides of the future embryonic brain and migrate toward the face where they will differentiate in a wide array of tissues including the facial bones. Disturbances in their development will lead to craniofacial defects including cleft palates and lips. There are many environmental and genetic causes that can lead to defects in craniofacial development. Our hypothesis is that a poorly describe gene, Limb bud and heart (Lbh) is critical for craniofacial development and that mutation affecting the dose or the sequence of this gene will lead to congenital craniofacial disease. This hypothesis is based on our preliminary observations that the loss of Lbh in both fish and frogs, two vertebrate model of development, leads to abnormal craniofacial development. This proposal will investigate the consequences of the loss of Lbh to CNC migration and craniofacial development.
This first Aim will identify how cells are affected by the loss of Lbh. More specifically, we will investigate if the loss of Lbh affect CNC cell movement, cell proliferation or cell death. We will also test whether the expression of selected genes that are known for their role in CNC development is lost in the absence of Lbh.
The second Aim will investigate the molecular mechanism by which Lbh, a putative transcription co-activator, function during CNC development. We will identify the amino acids of Lbh that are required for its function, and determine whether Lbh functions in the nucleus, in the cytoplasm or in both. Finally we will identify proteins that associate with Lbh and determine their contribution to Lbh function during craniofacial development. Altogether, these experiments will determine the role of Lbh during craniofacial development and identify the molecular mechanism by which this role is achieved. This study will provide information invaluable to our understanding of normal CNC migration and craniofacial development, which is critical when investigating the genetic causes of craniofacial defects. In fact, several studies including ours have shown that too much of Lbh can cause heart disease, while too little produces severe defect in the development of the facial structures. Even a simple mutation of one amino acid sequence of Lbh can create severe facial anomalies. Thus understanding how the Lbh protein function will help refine its role in multiple health relevant problems including cancer, heart and craniofacial diseases.
The cranial neural crest is a migratory cell population critical for the formation of the entire face and skull of vertebrate embryos and any perturbation at any stage of their development will result in craniofacial defects. The proposed research aims to determine the mechanisms by which these cells move and direct craniofacial development. This information can be used to develop new therapies to ameliorate or prevent craniofacial defect or any diseases involving other type of migratory cells such as cancer metastasis.
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