Sensory evolution in blind cavefish is driven by early embryonic events during gastrulation and neurulation.

Natural variations in sensory systems constitute adaptive responses to the environment. Here, we compared sensory placode development in the blind cave-adapted morph and the eyed river-dwelling morph of Astyanax mexicanus Focusing on the lens and olfactory placodes, we found a trade-off between these two sensory components in the two morphs: from neural plate stage onwards, cavefish have larger olfactory placodes and smaller lens placodes. In a search for developmental mechanisms underlying cavefish sensory evolution, we analyzed the roles of Shh, Fgf8 and Bmp4 signaling, which are known to be fundamental in patterning the vertebrate head and are subtly modulated in space and time during cavefish embryogenesis. Modulating these signaling systems at the end of gastrulation shifted the balance toward a larger olfactory derivative. Olfactory tests to assess potential behavioral outcomes of such developmental evolution revealed that Astyanax cavefish are able to respond to a 105-fold lower concentration of amino acids than their surface-dwelling counterparts. We suggest that similar evolutionary developmental mechanisms may be used throughout vertebrates to drive adaptive sensory specializations according to lifestyle and habitat.

Inner retinal cell development is impaired in Smoky Joe chickens.

Many different components of the retina can be affected by inherited degenerative diseases causing blindness. Currently, 5 different mutant strains of chicken have already been studied as potential models for inherited retinal degeneration; however, the potential for the blind strain of White Leghorns, called Smoky Joe (SJ), as a model remains unknown. Ocular symptoms observed within homozygous SJ birds show the birds have varying levels of blindness at hatch and by 8 wk posthatch are completely blind, but details about the development of the blindness are unclear (Salter et al., 1997). The objective of this study was to characterize the retinal development of blind and sighted SJ chicks during embryogenesis, and to monitor the numbers of the retinal cells with cell-type-specific markers. Blind SJ chicks showed less retinal cells throughout embryogenesis compared with sighted SJ chicks (P < 0.0001). Based on the histological analysis, it was determined that amacrine cells within the inner nuclear layer were the most affected cell type, showing lower numbers in the blind SJ compared with the sighted; amacrine cell development was also delayed in the blind birds, beginning 2 d later than in sighted SJ birds. Photoreceptors were also scarcely detected within the blind SJ and potentially may be an additional target of developmental impairment. Further analysis on posthatch SJ will aid in determining degenerative characteristics of a fully developed retina and its cells.

Retina-specific activation of a sustained hypoxia-like response leads to severe retinal degeneration and loss of vision.

Loss of vision and blindness in human patients is often caused by the degeneration of neuronal cells in the retina. In mouse models, photoreceptors can be protected from death by hypoxic preconditioning. Preconditioning in low oxygen stabilizes and activates hypoxia inducible transcription factors (HIFs), which play a major role in the hypoxic response of tissues including the retina. We show that a tissue-specific knockdown of von Hippel-Lindau protein (VHL) activated HIF transcription factors in normoxic conditions in the retina. Sustained activation of HIF1 and HIF2 was accompanied by persisting embryonic vasculatures in the posterior eye and the iris. Embryonic vessels persisted into adulthood and led to a severely abnormal mature vessel system with vessels penetrating the photoreceptor layer in adult mice. The sustained hypoxia-like response also activated the leukemia inhibitory factor (LIF)-controlled endogenous molecular cell survival pathway. However, this was not sufficient to protect the retina against massive cell death in all retinal layers of adult mice. Caspases 1, 3 and 8 were upregulated during the degeneration as were several VHL target genes connected to the extracellular matrix. Misregulation of these genes may influence retinal structure and may therefore facilitate growth of vessels into the photoreceptor layer. Thus, an early and sustained activation of a hypoxia-like response in retinal cells leads to abnormal vasculature and severe retinal degeneration in the adult mouse retina.

Taste bud development and patterning in sighted and blind morphs of Astyanax mexicanus.

In the blind cave-dwelling morph of A. mexicanus, the eye degenerates while other sensory systems, such as gustation, are expanded compared to their sighted (surface-dwelling) ancestor. This study compares the development of taste buds along the jaws of each morph. To determine whether cavefish have an altered onset or rate of taste bud development, we fluorescently labeled basal and receptor cells within taste buds over a developmental series. Our results show that taste bud number increases during development in both morphs. The rate of development is, however, accelerated in cavefish; a small difference in taste bud number exists at 5 dpf reaching threefold by 22 dpf. The expansion of taste buds in cavefish is, therefore, detectable after the onset of eye degeneration. This study provides important insights into the timing of taste bud expansion in cavefish as well as enhances our understanding of taste bud development in teleosts in general.

Infant neurodevelopment following fetal growth restriction: relationship with antepartum surveillance parameters.

OBJECTIVES: To evaluate the relationship between fetal Doppler parameters, biophysical profile score (BPP) and neurodevelopmental delay at 2 years of corrected age in infants who had been growth-restricted in utero. METHODS: This was a prospective observational study including 113 pregnancies complicated by intrauterine growth restriction (IUGR) (abdominal circumference<5th percentile and elevated umbilical artery (UA) pulsatility index). The relationships of UA, middle cerebral artery and ductus venosus (DV) Doppler features, BPP, birth acidemia (artery pH<7.0+/or base deficit>12), gestational age at delivery, birth weight and neonatal morbidity (i.e. bronchopulmonary dysplasia, >Grade 2 intraventricular hemorrhage, or necrotizing enterocolitis) with a 2-year neurodevelopmental delay were evaluated. Best Beginnings Developmental Screen, Bayley Scale of Infant Development II (BSID) and Clinical Adaptive/Clinical Linguistic Auditory Milestone Stage were used. BSID<70, cerebral palsy, abnormal tone, hearing loss and/or blindness defined neurodevelopmental delay. RESULTS: Seventy-two of the 113 pregnancies completed assessment; there were 10 stillbirths, 19 neonatal deaths, three infant deaths and nine pregnancies with no follow-up. Twenty fetuses (27.8%) had UA reversed end-diastolic velocity (REDV), 34 (47.2%) abnormal DV Doppler features and 31 (43.1%) an abnormal BPP. Median gestational age at delivery and birth weight were 30.4 weeks and 933 g, respectively. Twelve infants had acidemia and 28 neonatal morbidity. There were 38 (52.8%) infants with neurodevelopmental delay, including 37 (51.4%) with abnormal tone, 20 (27.8%) with speech delay, 23 (31.9%) with an abnormal neurological examination, eight (11.1%) with a hearing deficit and six (8.3%) with cerebral palsy. Gestational age at delivery was associated with cerebral palsy (r2=0.52, P<0.0001; 92% sensitivity and 83% specificity for delivery at <27 weeks). UA-REDV was associated with global delay (r2=0.31, P=0.006) and birth weight with neurodevelopmental delay (r2=0.54, P<0.0001; 82% sensitivity and 64% specificity for BW<922 g). CONCLUSIONS: Although UA-REDV is an independent contributor to poor neurodevelopment in IUGR no such effect could be demonstrated for abnormal venous Doppler findings or BPP. Gestational age and birth weight remain the predominant factors for poor neurodevelopment in growth-restricted infants.

Developmental mechanisms for retinal degeneration in the blind cavefish Astyanax mexicanus.

The sighted surface-dwelling (surface fish, SF) and the blind cave-living (cavefish, CF) forms of Astyanax mexicanus offer a unique opportunity to study the evolutionary changes in developmental mechanisms that lead to retinal degeneration. Previous data have shown the role of increased midline Sonic Hedgehog (Shh) signalling in cavefish eye degeneration (Yamamoto et al. [2004] Nature 431:844-847). Here, we have compared the major steps of eye development in SF and CF between 14 hours and 5 days of development. We have analyzed cell proliferation through PCNA and phospho-histone H3 staining and apoptosis through TUNEL and live LysoTracker analysis. We have assessed the expression of the major eye development signalling factors Shh and Fgf8, and the eye patterning genes Pax6, Lhx2, Lhx9, and Vax1, together with the differentiation marker GAD65. We show that eye development is retarded in CF and that cell proliferation in CF retina is proportionately similar to SF during early development, yet the retina degenerates after massive apoptosis in the lens and widespread cell death throughout the neuroretina. Moreover, and surprisingly, the signalling, patterning, and differentiation processes leading to the establishment of retinal layers and cell types happen almost normally in CF, although some signs of disorganization, slight heterochronies, and a lack of expression gradients are observable. Our data demonstrate that the evolutionary process of eye degeneration in the blind CF does not occur because of patterning defects of the retina and are consistent with the proposed scenario in which the trigger for eye degeneration in CF is lens apoptosis.

Hedgehog signalling controls eye degeneration in blind cavefish.

Hedgehog (Hh) proteins are responsible for critical signalling events during development but their evolutionary roles remain to be determined. Here we show that hh gene expression at the embryonic midline controls eye degeneration in blind cavefish. We use the teleost Astyanax mexicanus, a single species with an eyed surface-dwelling form (surface fish) and many blind cave forms (cavefish), to study the evolution of eye degeneration. Small eye primordia are formed during cavefish embryogenesis, which later arrest in development, degenerate and sink into the orbits. Eye degeneration is caused by apoptosis of the embryonic lens, and transplanting a surface fish embryonic lens into a cavefish optic cup can restore a complete eye. Here we show that sonic hedgehog (shh) and tiggy-winkle hedgehog (twhh) gene expression is expanded along the anterior embryonic midline in several different cavefish populations. The expansion of hh signalling results in hyperactivation of downstream genes, lens apoptosis and arrested eye growth and development. These features can be mimicked in surface fish by twhh and/or shh overexpression, supporting the role of hh signalling in the evolution of cavefish eye regression.

One eye but no vision: cave fish with induced eyes do not respond to light.

One of the most intriguing questions in evolutionary biology is the degree to which behavior is a necessary consequence of morphology. We explore this issue by examining phototactic behavior in epigean (eyed surface-dwelling) and troglomorphic (blind cave) forms of the teleost Astyanax fasciatus whose eyes were modified during embryogenesis by removing one or both lens vesicles from the epigean form or by transplanting the lens vesicle from an epigean fish into the optic cup of a blind cave form. Lens removal results in eye degeneration and blindness in adult epigean fish, whereas lens transplantation stimulates growth of the eye, inducing the development of optic tissues in the normally eyeless adult cave fish. Photoresponsiveness was examined by placing fish in an aquarium with one half illuminated and the other half dark and scoring their presence in the illuminated or dark half. Both the eyeless epigean fish and cave fish with induced eyes are indifferent to the illumination whereas the surface forms are scotophilic, suggesting that optic development and phototactic behavior are decoupled.

[Perspectives in the rehabilitation of vision in blind subjects]. / Perspectives en réhabilitation de la vision chez l'aveugle.

The normal development of the visual system from birth until the end of the critical period involves, for the young subject to achieve a number of visual experiments. In cases of late blindness, the visual system has been normally developed, which is not the case when early blindness is considered where an abnormal cerebral organization exists. Accordingly, attempts to rehabilitate vision in the blind have to consider these discrepancies. When the invasive visual prosthesis acting by electrical stimulation of spared parts of the visual system is suitable in case of late blindness, sensory substitution prostheses coding visual information into signals addressing an intact sensory modality seems devoted to cases of early blindness. This later approach takes into account the early blind's brain specific organization, whose undeveloped occipital cortex has been shown to be involved in the sensory substitution process using positron emission tomography.

The ocular pathology of Norrie disease in a fetus of 11 weeks' gestational age.

The ocular pathology of Norrie disease was studied for the first time in a fetus of 11 weeks' gestation, following prenatal diagnosis using genetic markers for Norrie disease and elective abortion. The eyes were histologically normal, with no evidence of primary neuroectodermal maldevelopment of the retina, previously postulated to be the cause of the ocular changes. We believe that the retinal and other manifestations of Norrie disease are the result of a primary abnormality of vascular proliferation, probably in relation to persistent hyperplastic primary vitreous after approximately 14 weeks' gestation. We postulate that the ocular and otological effects of Norrie disease may be due to a genetically mediated abnormality of secretion of, or sensitivity to, angiogenic growth factors at endodermal-neuroectodermal interfaces during fetal and postnatal development.

The development of the eye in Astyanax mexicanus (Characidae, Pisces), its blind cave derivative, Anoptichthys jordani (Characidae, Pisces), and their crossbreds. A scanning- and transmission-electron microscopic study.

The development of the eye of the characin Astyanax mexicanus, of its blind derivative Anoptichthys jordani, and crossbreds of both forms was studied at different ontogenetic stages by means of scanning- and transmission-electron microscopy. Astyanax exhibits a form of eye development resembling that in other characid species. A severe reduction of the eye could be observed in Anoptichthys starting with the second day of ontogeny. This degenerational process is characterized by the following features: 1) An overgrowth of epidermal tissue that gradually covers the surface of the eyeball; 2) the sinking of the eyeball below the surface of the integument; 3) the formation of epidermal channels from the body surface to the disappearing surface of the eyeball; 4) a severe degeneration of the retinal sensory cells; and 5) a small number of pigment granules in the pigment epithelial cells. The progeny of crosses between Astyanax and Anoptichthys show varying degrees of these degenerational signs. Taste buds and the lateral line organ display identical features in all crosses analyzed with the scanning electron microscope.