epidermal-growth-factor and Eye-Abnormalities

Axenfeld-Rieger syndrome (ARS) is a heterogeneous clinical entity transmitted in an autosomal dominant manner. The main feature, Axenfeld-Rieger Anomaly (ARA), is a malformation of the anterior segment of the eye that can lead to glaucoma and impair vision. Extra-ocular defects have also been reported. Point mutations of FOXC1 and PITX2 are responsible for about 40% of the ARS cases. We describe the phenotype of a patient carrying a deletion encompassing the 4q25 locus containing PITX2 gene. This child presented with a congenital heart defect (Tetralogy of Fallot, TOF) and no signs of ARA. He is the first patient described with TOF and a complete deletion of PITX2 (arr[GRCh37]4q25(110843057-112077858)x1, involving PITX2, EGF, ELOVL6 and ENPEP) inherited from his ARS affected mother. In addition, to our knowledge, he is the first patient reported with no ocular phenotype associated with haploinsufficiency of PITX2. We compare the phenotype and genotype of this patient to those of five other patients carrying 4q25 deletions. Two of these patients were enrolled in the university hospital in Toulouse, while the other three were already documented in DECIPHER. This comparative study suggests both an incomplete penetrance of the ocular malformation pattern in patients carrying PITX2 deletions and a putative association between TOF and PITX2 haploinsufficiency.

Topics: Acetyltransferases; Adult; Anterior Eye Segment; Child; Chromosome Deletion; Chromosomes, Human, Pair 4; Epidermal Growth Factor; Eye Abnormalities; Eye Diseases, Hereditary; Fatty Acid Elongases; Female; Glutamyl Aminopeptidase; Haploinsufficiency; Homeobox Protein PITX2; Homeodomain Proteins; Humans; Male; Pedigree; Phenotype; Tetralogy of Fallot; Tooth Abnormalities; Transcription Factors

The fetal development of the mammalian eyelid involves the expansion of the epithelium over the developing cornea, fusion into a continuous sheet covering the eye, and a splitting event several weeks later that results in the formation of the upper and lower eyelids. Recent studies have revealed a significant number of molecular signaling components that are essential mediators of eyelid development. Receptor-mediated sphingosine 1-phosphate (S1P) signaling is known to influence diverse biological processes, but its involvement in eyelid development has not been reported. Here, we show that two S1P receptors, S1P2 and S1P3, are collectively essential mediators of eyelid closure during murine development. Homozygous deletion of the gene encoding either receptor has no apparent effect on eyelid development, but double-null embryos are born with an "eyes open at birth" defect due to a delay in epithelial sheet extension. Both receptors are expressed in the advancing epithelial sheet during the critical period of extension. Fibroblasts derived from double-null embryos have a deficient response to epidermal growth factor, suggesting that S1P2 and S1P3 modulate this essential signaling pathway during eyelid closure.

Topics: Animals; Blotting, Western; Cells, Cultured; Embryo, Mammalian; Embryonic Development; Epidermal Growth Factor; Eye Abnormalities; Eyelids; Female; Fibroblasts; Gene Expression Regulation, Developmental; In Situ Hybridization; Lysophospholipids; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Pregnancy; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors

In an emerging model, area patterning of the mammalian cerebral cortex is regulated in part by embryonic signaling centers. Two have been identified: an anterior telencephalic source of fibroblast growth factors and the cortical hem, a medial structure expressing winglessint (WNT) and bone morphogenetic proteins. We describe a third signaling source, positioned as a mirror image of the cortical hem, along the lateral margin of the cortical primordium. The cortical antihem is identified by gene expression for three epidermal growth factor (EGF) family members, Tgf(alpha), Neuregulin 1, and Neuregulin 3, as well as two other signaling molecules, Fgf7 and the secreted WNT antagonist Sfrp2. We find that the antihem is lost in mice homozygous for the Small eye (Pax6) mutation and suggest the loss of EGF signaling at least partially explains defects in cortical patterning and cell migration in Small eye mice.

Topics: Animals; Carrier Proteins; Cell Movement; Cerebral Cortex; Epidermal Growth Factor; Eye Abnormalities; Eye Proteins; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Homeodomain Proteins; Homozygote; In Situ Hybridization; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Mice, Mutant Strains; Morphogenesis; Multigene Family; Neuregulin-1; Neuregulins; Paired Box Transcription Factors; PAX6 Transcription Factor; Proteins; Repressor Proteins; RNA, Messenger; Signal Transduction; Transcription Factors; Transforming Growth Factor alpha

Mice homozygous for a disrupted transforming growth factor alpha (TGF alpha) gene are healthy and fertile, although some older mice show evidence of corneal inflammation. In contrast with TGF alpha +/- and +/+ animals, TGF alpha -/- mice have a pronounced waviness of the coat. Histological examination of the skin from TGF alpha -/- mice reveals a dramatic derangement of hair follicles. Mice with a disrupted TGF alpha gene also have curly whiskers, first evident on the day of birth. The phenotype of TGF alpha -/- mice is remarkably similar to that of the mouse mutant waved-1 (wa-1). Offspring resulting from crosses between TGF alpha -/- and wa-1 mice display the curly whisker-coat phenotype, indicating that the basis of the wa-1 phenotype is a mutation in the TGF alpha gene. These observations suggest that TGF alpha plays a pivotal role in determining skin architecture and in regulating hair development.

Topics: Animals; Base Sequence; Chimera; Epidermal Growth Factor; Epithelial Cells; Eye Abnormalities; Female; Gene Deletion; Hair; Keratitis; Male; Mice; Mice, Mutant Strains; Molecular Sequence Data; Mutagenesis, Insertional; Mutation; Oligodeoxyribonucleotides; Skin; Skin Diseases; Transforming Growth Factor alpha; Vibrissae; Wound Healing