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Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder. ARS is considered to be fully penetrant, but variable expressivity was reported in families. The three cardinal features of ARS include specific ocular anomalies of the anterior segment, dental anomalies and redundant periumbilical skin. A variety of other abnormalities have been reported in ARS patients such as pituitary, hearing, heart and limb defects that may represent coincidental findings in some cases and be associated with specific mutations in others. Identification of genes and chromosomal regions associated with ARS demonstrated extreme genetic heterogeneity of this condition and allowed genotype-phenotype correlation studies. In this chapter, we describe identification of a gene, , which to-date represents a major gene for Axenfeld-Rieger syndrome accounting for approximately 40% of mutations in classic ARS patients. The gene was discovered by positional cloning approach and is located at 4q25 in humans. The gene appears to play an important role in development of many different systems and its involvement in human disorders needs to be further elucidated.

A second locus for Rieger syndrome (RS) was identified from chromosomal abnormalities involving chromosome 6p25. Study of the breakpoint revealed mutations in the forkhead transcription factor () gene. Initially, this defect was identified in two patients with RS and glaucoma and later FOXC1 mutations were associated with RS patients. Several studies have shown linkage of anterior segment abnormalities to the same region of chromosome 6. These abnormalities include Axenfeld anomaly, Rieger anomaly, iridogoniodysgenesis anomaly and familial glaucoma iridogoniodysplasia. Axenfeld-Rieger syndrome (ARS) is a heterogeneous condition as noted by the identification of different chromosomal aberrations and phenotypes of ARS patients. This chapter will focus on the identification of and its association with the group of disorders that comprise Axenfeld-Rieger syndrome.

The anomalies in most of the involved tissues in Rieger syndrome (anterior segment of the eye, cranial bones, teeth, periumbilical skin) are derived from the neural crest. If expression in the neuroectoderm includes the neural crest, most of the Rieger-anomalies could be explained by a deletion. However, little is known about the behavior of cells within the human anterior neural tube and the molecular action of PAX6 has not been determined.

Mutations in the homeobox gene are associated with Axenfeld-Rieger syndrome (ARS) and provided the first link of this transcription factor to tooth, eye, heart, and pituitary development. We are investigating the molecular basis of developmental anomalies associated with human mutations. PITX2 mutant proteins exhibit a variety of transcriptional defects including, instability, decreased DNA binding activity, DNA binding without transcriptional activation, phosphorylation defects, increased transcriptional and dominant negative activities. ARS is a haploinsufficiency disorder and because PITX2 proteins can dimerize the effects of the mutations can cause heterogeneous developmental anomalies in these patients. is a member of the Forkhead Box transcription factor family that play key roles in development, including morphogenesis and cell fate specification. mutations are associated with ARS and Axenfeld-Rieger Anomaly (ARA) that result in a spectrum of glaucoma phenotypes in humans. Missence mutations in the FOXC1 forkhead domain result in impaired DNA binding and reduced transactivation of target genes. is a homeobox gene and recently a mutation in this transcription factor has been linked to Rieger syndrome. This report will summarize the molecular/biochemical mechanism of these developmental transcription factors and how they correlate with the clinical manifestations of ARS and ARA.

The pituitary gland is a neuroendocrine organ composed of specialized peptide hormone-producing cells that control many bodily functions. Pituitary development depends on the combined activity of extrinsic signaling molecules and intrinsic transcription factors. One of the earliest acting transcription factors in pituitary development is PITX2, a homeobox transcription factor required for expansion of the pituitary primordium, Rathke’s pouch. Analysis of an allelic series in mice revealed that pituitary gland size and the specification of individual pituitary cell types are also dependent upon , and this dependence is sensitive to gene dosage. Mechanistically this pituitary phenotype results from the inability of low levels of PITX2 to activate gene expression of several lineage specific transcription factors, such as and . Our understanding gene dosage effects on pituitary development suggests a basis for dosage sensitive defects in other organs of Rieger syndrome patients. In addition, analysis of the allelic series in mice raises the possibility of gonadotropin and PIT1 lineage defects in individuals with loss of PITX2 function.

Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder. ARS is considered to be fully penetrant, but variable expressivity was reported in families. The three cardinal features of ARS include specific ocular anomalies of the anterior segment, dental anomalies and redundant periumbilical skin. A variety of other abnormalities have been reported in ARS patients such as pituitary, hearing, heart and limb defects that may represent coincidental findings in some cases and be associated with specific mutations in others. Identification of genes and chromosomal regions associated with ARS demonstrated extreme genetic heterogeneity of this condition and allowed genotype-phenotype correlation studies. In this chapter, we describe identification of a gene, , which to-date represents a major gene for Axenfeld-Rieger syndrome accounting for approximately 40% of mutations in classic ARS patients. The gene was discovered by positional cloning approach and is located at 4q25 in humans. The gene appears to play an important role in development of many different systems and its involvement in human disorders needs to be further elucidated.

is a -related homeobox gene that has been shown to be the mutated gene in Axenfeld-Rieger syndrome (ARS). The focus of this chapter will be to review recent studies that address the role of in cardiac morphogenesis. Since ARS patients usually manifest ocular, dental and abdominal wall phenotypes, this review will deal primarily with experiments performed in model systems used to study gene function, such as the mouse.

The transcriptional mechanisms underlying tooth development are only beginning to be understood. Axenfeld-Rieger syndrome (ARS) patients provided the first link of to tooth development. ARS patients present clinically with dental hypoplasia, which includes microdontia, hypodontia and misshapen teeth. is the earliest known transcription factor that is selectively expressed in the oral ectoderm. Since and are expressed in the dental epithelium we are examining the transcriptional activity of PITX2 in concert with these factors. We demonstrate that Msx2 binds to a variety of DNA elements and may play a more central role in regulating genes in tissues expressing this transcriptional repressor. We have identified the promoter as a target of PITX2 during tooth development. Msx2 represses the promoter and coexpression of both PITX2 and Msx2 resulted in transcriptional antagonism of the promoter. Furthermore, a mutation associated with ARS () is unable to transactivate the promoter. ARS patients with this point mutation present clinically with missing teeth. In contrast, a patient that presents clinically with only iris hypoplasia and normal tooth development has a mutation () that transactivates the promoter. These data suggest a molecular mechanism for the dental anomalies associated with Axenfeld-Rieger syndrome. We will review the role of in tooth development and speculate on potential downstream targets of PITX2.

The anterior segment of the vertebrate eye is a complex arrangement of interdependent tissues of different embryonic origins. Despite its critical role in normal vision, relatively little is currently known about the development of the anterior segment and its molecular determinants. All three members of the homeobox-containing transcription factor gene family were found to be expressed in the anterior segment structures during embryonic development. Two of these genes, and , were shown to be responsible for a spectrum of developmental anterior segment phenotypes associated with glaucoma, corneal opacities and cataracts in humans and mice. These findings demonstrate a requirement of genes for normal development of the anterior segment of the eye and provide tools to study the molecular control of development of these structures.

We analyse the bifurcation sequence of typical simple plane shear flows numerically by using a bifurcation analysis and also a DNS technique, considering flows with and without a system rotation about a spanwise axis. Our analysis is applied to (1) plane Couette flow, (2) plane Poiseuille flow, and (3) flow with a cubic velocity profile.