DIX5 HOMEOBOX GENE CONTROL OF CRANIOFACIAL MORPHOGENESIS

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Fetal development of the mammalian craniofacial region is a complex embryological process which is poorly understood at the molecular level. Early in embryonic life the mammalian craniofacial region is first manifested as a blastema-like structure of paired branchial arches comprised primary of neural crest-derived mesenchymal cells. These neural crest cells acquires some of their patterning information prior to emigration from the hindbrain, and additional patterning information is imparted to them during their migration into the branchial arches. Several homeobox-containing DNA-binding transcriptional regulations have been identified which direct certain aspects of the morphogenesis and cellular differentiation of the craniofacial region. Here we describe a Dlx5 a new homeobox-containing gene of the distal less (Dlx) family which is most strongly expressed in the mesenchyme of the developing craniofacial region. Based upon its embryonic expression pattern, and the mode of action of other Dlx homeobox-contain genes, Dlx5 has the potential of being a major director normal morphogenesis and cellular differentiation of branchial arch derived structures. To understand the genetic basis of embryonic development of the craniofacial region, we propose to alter the normal function of the homeobox Dlx5 which shows highly restricted expression in the branchial arches (as well as the perichondrial region of all skeletal elements). In addition, we will identify and characterize the DNA cis-regulatory elements which direct regionally-restricted Dlx5 gene expression in the developing craniofacial region. To this end, we will rely primarily on the transgenic mouse technology that we have developed and refined over the last eight years. Accordingly, (I) we will generate a disruption (gene knock-out) of Dlx5. (II) We will determine the DNA regulatory elements which control Dlx5 craniofacial-specific gene expression. Results of these experiments will help clarify the role of Dlx5 in normal craniofacial morphogenesis. This is in keeping with our long range goal which is to understand the molecular mechanisms involved in directing mammalian craniofacial development with the belief that such knowledge will eventually be used to correct either trauma to, or genetic defects of the craniofacial region.