Defects In Eye Development Research Articles

Environmental risk factors in congenital malformations of the eye

Developmental eye defects such as coloboma are a significant cause of visual morbidity in children, and are more common in India than elsewhere. The possible role of environmental factors in the aetiology of these conditions was investigated by studying birth order, symptoms of vitamin A deficiency (night blindness), drug use and maternal illness in pregnancy, rubella antibodies and exposure to agricultural chemicals. Through hospital records and community-based rehabilitation programmes in Andhra Pradesh, children with colobomata were recruited from schools for the blind. Eighty-three mothers of affected children were interviewed. The results showed that 43% of parents were consanguineous, that 19% had a positive family history and that the frequency of coloboma was highest in second-born children. Eleven (16%) mothers had a history of night blindness while pregnant with the affected child; seven (8%) took medication during the 1st trimester, abortifacients in two cases; three reported fever in the 1st trimester; and 11 (13%) reported exposure to agricultural chemicals.

The complexities of ocular genetics.

The cliché 'a picture is worth a thousand words' is a testament to the power of the visual system in helping us deal with our physical environment. Rarely do perturbations to the visual system, even minor ones, go unnoticed. Major defects in eye development may occur in the absence of systemic problems which threaten health. Ocular anomalies offer a window into many developmental events which would otherwise be difficult to study.

A capture-recapture model to estimate prevalence of children born in Scotland with developmental eye defects.

Microphthalmia, anophthalmia and coloboma (MAC) are closely related structural developmental eye defects that have caused public concern in the UK following media reports of apparent clusters of cases. An extensive search was carried out to identify potential cases, and diagnoses were confirmed by ophthalmological review. Despite this effort, it was recognised that some cases would remain unidentified. Capture-recapture methods could improve the accuracy of the study's birth prevalence estimate. A register of all children born with the developmental eye defects of MAC in Scotland (1981-96) was compiled. This identified 188 cases from eight national ascertainment sources. The methods described by Hook and Regal were used to determine possible estimates for each source. A log-linear method of capture-recapture was used to fit a model to the number of children identified by the different combinations of the eight national sources, and the individual sources were included in the model as main effects. Maximum-likelihood estimates were calculated for tables of captured/not captured by one source versus any other source. The estimated number of unobserved cases for the most complete source, the register of congenital anomalies for Scotland, and the seven others combined is 78 (95% CI 53-115). Estimates calculated from two different log-linear models of the numbers of cases unobserved by all sources were 61 (95% CI 43-86) and 175 (95% CI 106-287). An external check with an independent congenital-anomalies register in one region, which is known to have high completeness, gave an estimate of 120. The study found a birth prevalence of MAC in Scotland of 1.9/10000, based on total live births during the study period. The capture-recapture analysis suggests that the true birth prevalence lies between 2.4/10 000 and 3.5/10000. Our experience shows that, even with multiple sources of ascertainment and considerable resources directed at case identification, a considerable level of under-ascertainment of congenital eye-anomalies still results, and suggests that the use of capture-recapture analysis would be a useful addition to congenital anomalies registers for needs assessment, disease-burden estimates and health-service planning.

Targeted mutations of transforming growth factor‐β genes reveal important roles in mouse development and adult homeostasis

Transforming growth factors-beta (TGF-beta) are multifunctional molecules with profound biological effects in many developmental processes including regulation of cell proliferation, differentiation, cell adhesion, skeletal development, haematopoiesis, inflammatory responses, and wound healing. To learn about the role of TGF-beta in vivo, phenotypes of targeted mutations of molecules within the TGF-beta signalling pathway, TGF-beta1, -beta2, -beta3, TGF-beta receptor (TbetaR-II) and the signalling molecules SMAD2, SMAD3 and SMAD4, are discussed in this review. The three individual TGF-beta mutants show distinct and only partially overlapping phenotypes. In mice, targeted disruption of the TGF-beta1 gene results in diffuse and lethal inflammation about 3 weeks after birth, suggesting a prominent role of TGF-beta in the regulation of immune cell proliferation and extravasation into tissues. However, just half of the TGF-beta1 (-/-) conceptuses actually reach partuition due to defective haematopoiesis and endothelial differentiation. Targeted disruption of both TGF-beta2 and TGF-beta3 genes results in perinatal lethality. TGF-beta2 null mice exhibit a broad range of developmental defects, including cardiac, lung, craniofacial, limb, eye, ear and urogenital defects, whereas TGF-beta3 gene ablation results exclusively in defective palatogenesis and delayed pulmonary development. The TbetaR-II null phenotype closely resembles that of TGF-beta1 (-/-) conceptuses, which die in utero by E10.5. Loss of SMAD2 or SMAD4 results in related phenotypes: the mutants fail to form an organized egg cylinder, lack mesoderm required for gastrulation and die prior to E8.5. Together, gene ablation within the TGF-beta signalling pathway supports the notion of a prominent role of TGF-beta during development.

Developmental eye and neural tube defects in the eye blebs mouse.

In the mouse, eye blebs (eb) is a spontaneous mutation that presents a useful model for the study of abnormal eye development. Since its initial description three decades ago, little information has been generated regarding the developmental course of eb eyes. Although the gene for eb has not been identified, much can be learned from the developmental defects present in the eb mouse. First detected in the eye at embryonic day 11.5 (E11.5), the eb defect is observed as an increased vascularization throughout the developing eye and head region. As development proceeds, the embryonic eye fills with blood, and the resulting hematoma distorts the shape of the iris. The eyelids fail to close, and animals are born with open eyes. Lens degeneration and retinal folding are characteristic of eb, as are microphthalmia and thick, disorganized irises. A second presentation of the eb defect is disruption of neural tube closure in the anterior and hindbrain neuropores. These eb animals are born with open neural tubes but with apparently normal eyes.

The Forkhead/Winged Helix Gene Mf1 Is Disrupted in the Pleiotropic Mouse Mutation congenital hydrocephalus

Mf1 encodes a forkhead/winged helix transcription factor expressed in many embryonic tissues, including prechondrogenic mesenchyme, periocular mesenchyme, meninges, endothelial cells, and kidney. Homozygous null Mf1lacZ mice die at birth with hydrocephalus, eye defects, and multiple skeletal abnormalities identical to those of the classical mutant, congenital hydrocephalus. We show that congenital hydrocephalus involves a point mutation in Mf1, generating a truncated protein lacking the DNA-binding domain. Mesenchyme cells from Mf1lacZ embryos differentiate poorly into cartilage in micromass culture and do not respond to added BMP2 and TGFbeta1. The differentiation of arachnoid cells in the mutant meninges is also abnormal. The human Mf1 homolog FREAC3 is a candidate gene for ocular dysgenesis and glaucoma mapping to chromosome 6p25-pter, and deletions of this region are associated with multiple developmental disorders, including hydrocephaly and eye defects.

Dual functions of the Drosophila eyes absent gene in the eye and embryo

In eyes absent (eya) mutants, eye progenitor cells undergo cell death early in development. Whereas the phenotype of eya1 is limited to the eye, other mutations are lethal. Genetic and molecular analysis reveals that mutations in one region of the gene cause embryonic lethality, whereas mutations throughout the gene cause defects in eye development. Mosaic analysis indicates that the eya requirement is cell autonomous. In eye-specific mutants, expression in the eye disc is lacking while embryonic expression is normal. Both the type I and type II transcripts are expressed in the developing eye, and expression of either can rescue the eye phenotype. These data indicate a specific requirement for eya function in eye progenitor cells that is normally fulfilled by both transcripts.

Developmental malformations and intrauterine deaths in gamma-ray-irradiated scid mouse embryos

Purpose: To examine the induction by radiation of developmental malformations and intrauterine deaths in severe combined immunodeficiency (scid) mice. Materials and methods: The scid embryos, as well as those of C.B-17 control mice, were irradiated with graded doses of 60Co gamma-rays on gestation day 8. Results: Intrauterine deaths in scid mice increased with radiaton dose, and their frequency was substantially higher than in C.B-17 mice. The LD50 for intrauterine death in scid mice was 0.58 Gy and 1.25 Gy in C.B-17 mice. In addition, after irradiation scid mice showed several types of developmental malformations, including meningoencephalocele, spina bifida, eye defects, tail defects and oedema. Malformation incidences were higher in scid than in C.B-17 mice: 33.3% in scid mice irradiated with 0.75 Gy and 13.0% in C.B-17 mice irradiated with 1.0 Gy. However, when malformation incidences were plotted against intrauterine deaths, all the data, irrespective of the type of mouse, essentially fell along a single straight line. Conclusions: These results suggest that some mechanism common to both scid and normal mice induces developmental malformations. This mechanism involves cell killing. Residual DNA damage, such as double-strand breaks, could be associated with radiation-induced teratogenesis.

Cytoplasmic dynein function is essential in Drosophila melanogaster.

The microtubule motor cytoplasmic dynein has been implicated in a variety of intracellular transport processes. We previously identified and characterized the Drosophila gene Dhc64C, which encodes a cytoplasmic dynein heavy chain. To investigate the function of the cytoplasmic dynein motor, we initiated a mutational analysis of the Dhc64C dynein gene. A small deletion that removes the chromosomal region containing the heavy chain gene was used to isolate EMS-induced lethal mutations that define at least eight essential genes in the region. Germline transformation with a Dhc64C transgene rescued 16 mutant alleles in the single complementation group that identifies the dynein heavy chain gene. All 16 alleles were hemizygous lethal, which demonstrates that the cytoplasmic dynein heavy chain gene Dhc64C is essential for Drosophila development. Furthermore, our failure to recover somatic clones of cells homozygous for a Dhc64C mutation indicates that cytoplasmic dynein function is required for cell viability in several Drosophila tissues. The intragenic complementation of dynein alleles reveals multiple mutant phenotypes including male and/or female sterility, bristle defects, and defects in eye development.

Open brain, a new mouse mutant with severe neural tube defects, shows altered gene expression patterns in the developing spinal cord.

We describe a new mouse mutation, designated open brain (opb), which results in severe defects in the developing neural tube. Homozygous opb embryos exhibited an exencephalic malformation involving the forebrain, midbrain and hindbrain regions. The primary defect of the exencephaly could be traced back to a failure to initiate neural tube closure at the midbrain-forebrain boundary. Severe malformations in the spinal cord and dorsal root ganglia were observed in the thoracic region. The spinal cord of opb mutant embryos exhibited an abnormal circular to oval shape and showed defects in both ventral and dorsal regions. In severely affected spinal cord regions, a dorsalmost region of cells negative for Wnt-3a, Msx-2, Pax-3 and Pax-6 gene expression was detected and dorsal expression of Pax-6 was increased. In ventral regions, the area of Shh and HNF-3 beta expression was enlarged and the future motor neuron horns appeared to be reduced in size. These observations indicate that opb embryos exhibit defects in the specification of cells along the dorsoventral axis of the developing spinal cord. Although small dorsal root ganglia were formed in opb mutants, their metameric organization was lost. In addition, defects in eye development and malformations in the axial skeleton and developing limbs were observed. The implications of these findings are discussed in the context of dorsoventral patterning of the developing neural tube and compared with known mouse mutants exhibiting similar defects.

Effects of H-2 and Vitamin A on Eye Defects in Congenic Mice

Pregnant mice congenic with C57BL/10 (B10.A, B10.BR, B10.D2, B10.A(2R), B10.A(5R), B10.A(15R), B10.A(1R), B10.A(18R), and B10.OL) were fed Purina Mouse Chow or the same diet plus 200 IU of vitamin A daily. The pregnant dams were sacrificed on the 18th day of gestation and the fetuses were sexed and examined for defects in eye development. It was found that the frequency of microphthalmia and anophthalmia in the female progeny of mice fed Mouse Chow was 7.4-9.2% in B10.A and B10.BR, 4.0-5.5% in B10.A(18R), B10, B10.A(5R), B10.A(1R), B10.A(15R), and B10.A(2R), and 0.8% and 1.4% in B10.D2 and B10.OL mice, respectively. On average, the frequency of these defects in the female progeny was 6.2 times greater than that in males (P less than 0.001). The right eye was 5.8 times more often affected than the left (P less than 0.001). The addition of vitamin A to the diet increased the frequency of these eye abnormalities in all strains, suggesting that this effect is not mediated by loci associated with H-2, as is the case with vitamin A-enhanced cleft palate. The addition of vitamin A to the diet did not affect the ratios of affected males to females, affected right to left eye, or microphthalmia to anophthalmia. The results suggest that there are two loci on chromosome 17, one centromeric to E beta and one telemeric to C4, that interact to determine to some degree the frequency of microphthalmia and anophthalmia.