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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2009.10.029 Byline: L. Feng (a)(b), R.E. Hernandez (a)(b)(c), J.S. Waxman (d), D. Yelon (d), C.B. Moens (a)(b) Keywords: Zebrafish; Retinoic acid; dhrs3; Retinoid metabolism; Negative feedback; Nervous system development; Hindbrain; rdh10 Abstract: Retinoic acid (RA) is an important developmental signaling molecule responsible for the patterning of multiple vertebrate tissues. RA is also a potent teratogen, causing multi-organ birth defects in humans. Endogenous RA levels must therefore be tightly controlled in the developing embryo. We used a microarray approach to identify genes that function as negative feedback regulators of retinoic acid signaling. We screened for genes expressed in early somite-stage embryos that respond oppositely to treatment with RA versus RA antagonists and validated them by RNA in situ hybridization. Focusing on genes known to be involved in RA metabolism, we determined that dhrs3a, which encodes a member of the short-chain dehydrogenase/reductase protein family, is both RA dependent and strongly RA inducible. Dhrs3a is known to catalyze the reduction of the RA precursor all-trans retinaldehyde to vitamin A; however, a developmental function has not been demonstrated. Using morpholino knockdown and mRNA over-expression, we demonstrate that Dhrs3a is required to limit RA levels in the embryo, primarily within the central nervous system. Dhrs3a is thus an RA-induced feedback inhibitor of RA biosynthesis. We conclude that retinaldehyde availability is an important level at which RA biosynthesis is regulated in vertebrate embryos. Author Affiliation: (a) Division of Basic Science and HHMI, Fred Hutchinson Cancer Research Center, B2-152, 1100 Fairview Ave. N, Seattle, WA 98109, USA (b) Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA (c) Medical Scientist Training Program, University of Washington, Seattle, WA, USA (d) Developmental Genetics Program and Department of Cell Biology, Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA Article History: Received 14 July 2009; Revised 13 October 2009; Accepted 21 October 2009

BACKGROUND: Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed [...]

There is a concern that increased paternal age may be associated with altered fertility and an increased incidence of birth defects in man. In previous studies of aged male rats, we have found abnormalities in the fertility and in the embryos sired by older males. Aging in mammals is associated with alterations in the content and patterns of DNA methylation in somatic cells; however, little is known in regard to germ cells. A systematic search for global and gene-specific alterations of DNA methylation in germ cells and liver of male rats was done. Restriction landmark genomic scanning, a method used to determine specific methylation patterns of CpG island sequences, has revealed a region of the ribosomal DNA locus that is preferentially hypermethylated with age in both spermatozoa and liver. In contrast, all single copy CpG island sequences in spermatozoa and in liver remain unaltered with age. We further demonstrate that a large proportion of rat ribosomal DNA is normally methylated and that regional and site-specific differences exist in the patterns of methylation between spermatozoa and liver. We conclude that patterns of ribosomal DNA methylation in spermatozoa are vulnerable to the same age-dependent alterations that we observe in normal aging liver. Failure to maintain normal DNA methylation patterns in male germ cells could be one of the mechanisms underlying age-related abnormalities in fertility and progeny outcome.

Objective. To measure the primary and secondary school-age neurologic, cognitive, and educational outcomes in a cohort of extremely premature infants born after the introduction of exogenous surfactant therapy in a circumscribed region. Methods. Two hundred thirteen infants born at Results. One hundred thirty-two infants survived to school age, of whom 127 (96%) were evaluated in 1992-1995 and 126 (95%) were evaluated in 2000. Mean ages were 7.0 years at first follow-up and 14.1 years at second follow-up. At primary-school age follow-up, 19 children (15%) had cerebral palsy, 24 (19%) had a general cognitive index Conclusions. Premature infants born in the surfactant era remain at high risk of neurodevelopmental compromise. Although many of these children do well, a significant minority will require intensive special educational services through secondary school age. Pediatrics 2002; 110:1094-1102; premature infants, very low birth weight infants, follow-up studies, pulmonary surfactants, developmental disabilities., ABBREVIATIONS. GCI, General Cognitive Index; RDS, respiratory distress syndrome; NICU, neonatal intensive care unit; SMH, Strong Memorial Hospital; IVH, intraventricular hemorrhage; CI, confidence interval. The introduction of surfactant has dramatically [...]

Approximately 3% of children in developed countries are born with nongenetic birth defects. However, the nature and mechanisms of teratogenesis are poorly understood. We investigated mechanisms of teratogen-mediated blockade of maternofetal transport by screening a combinatorial library for peptides that bind nonendothelial placental vasculature in pregnant mice. Here, we identified a peptide motif, TPKTSVT, that homes to the yolk sac, induces placental necrosis, and disrupts embryo development. We show that TPKTSVT promotes transcytosis of phage into the embryo and blocks the transplacental transport of immunoglobulins. Based on these data, we propose a model in which TPKTSVT targets a placental Fc receptor. Absence of TPKTSVT placental homing in mice lacking [[beta].sub.2]-microglobulin ([[beta].sub.2]m) suggests FcRn/[[beta].sub.2]m as a target for the TPKTSVT, which is unexpected, given the normal development of FcRn/[[beta].sub.2]m-deficient progeny. High-throughput screening for embryotoxins that target placental receptors could be developed to systematically identify and avoid exposure to teratogenic drugs.

The biological basis or mechanism whereby folate supplementation protects against heart and neural tube defects is unknown. It has been hypothesized that the amino acid homocysteine may be the teratogenic agent, since serum homocysteine increases in folate depletion; however, this hypothesis has not been tested. In this study, avian embryos were treated directly with D,L-homocysteine or with L-homocysteine thiolactone, and a dose response was established. Of embryos treated with 50 [[micro]liter] of the teratogenic dose (200 mM D,L-homocysteine or 100 mM L-homocysteine thiolactone) on incubation days 0, 1, and 2 and harvested at 53 h (stage 14), 27% showed neural tube defects. To determine the effect of the teratogenic dose on the process of heart septation, embryos were treated during incubation days 2, 3, and 4; then they were harvested at day 9 following the completion of septation. Of surviving embryos, 23% showed ventricular septal defects, and 11% showed neural tube defects. A high percentage of the day 9 embryos also showed a ventral closure defect. The teratogenic dose was shown to raise serum homocysteine to over 150 nmol/ml, compared with a normal level of about 10 nmol/ml. Folate supplementation kept the rise in serum homocysteine to [approximately equal to]45 nmol/ml, and prevented the teratogenic effect. These results support the hypothesis that homocysteine per se causes dysmorphogenesis of the heart and neural tube, as well as of the ventral wall.

Histological analysis of the skeleton of mutant Hoxa-2 mice proves the existence of a branchial Hox code. The elements, usually derived from the second arch, are replaced by elements resembling more anterior structures such as Meckel's cartilage. Mice born with Hoxa-2 mutants consequently exhibit multiple cranial skeletal defects, accompanied by a cleft palate, and die within 24 hours of birth.

* This review of the Apert syndrome, based on our research experience with 136 cases, provides a clinically relevant pediatric perspective. The brain is megalencephalic, resulting in a disporportionately high cranium and a mean birth length and weight above the 50th percentile. The growth pattern in childhood consists of a slowing of linear growth so that most values fall between the 5th and 50th percentiles. From adolescence to adulthood, slowing becomes more pronounced. Central nervous system abnormalities may occur in some cases, including malformations of the corpus callosum and limbic structures, gyral abnormalities, hypoplastic white matter, and heterotopic gray matter. Distortion ventriculomegaly is found because of the large brain in a misshapen skull. Progressive hydrocephalus is uncommon. intelligence in patients with the Apert syndrome varies from normality to mental deficiency. Early release of the coronal suture and advancement and reshaping of the frontal bone reduce further dysmorphic and unwanted growth changes in the skull, but probably do not affect mentation. Associated cardiovascular and genitourinary anomalles occur in 10% and 9.6% of cases, respectively. Other important findings reviewed include upper- and lower-airway compromise, calvarial development, cervical vertebral anomalies, limb defects, ocular and otologic manifestations, and dermatologic characteristics. (AJDC. 1993;147:989-993), The Apert syndrome is a genetic disorder characterized by a misshapen skull and syndactyly, or webbed fingers and toes. Research on 136 cases of Apert syndrome has provided information on a variety of associated structural and physiological abnormalities. Birth weight and length are usually above normal because of an overly large brain and high skull, but growth in childhood is usually between the 5th and 50th percentiles. Patients may have normal intelligence, but often display some degree of mental deficiency, from mild to severe. Surgery to correct abnormal skull fusion may be desirable, but does not seem to alter intelligence level. Two-thirds of patients have stiffness of the neck, resulting from fusion of cervical vertebrae. Approximately 10% of patients have defects of their cardiovascular or genitourinary systems. Apert syndrome may also affect the respiratory system, the eyes, skin and hearing.

A major cause of loss of vision in childhood is hypoplasia (underdevelopment) of the optic nerve. This is a birth defect resulting from damage at any point along the developing visual pathways. Optic nerve hypoplasia may be associated with other important abnormalities in the nervous and endocrine systems. A study was undertaken to determine the factors involved when optic nerve hypoplasia and central nervous system disorders occur simultaneously, and to describe the association with vascular encephalopathies (brain abnormalities due to blood-vessel disorders). Forty-six children with bilateral optic nerve hypoplasia were studied; 32 children were born at full term, and 14 were born prematurely. Thirty-two of the 46 children (69.5 percent) had associated neurodevelopmental handicaps. A CT scan revealed that 90 percent of these neurodevelopmentally handicapped children had structural central nervous system abnormalities. Neurodevelopmental handicap occurred more often in the premature babies (86 percent) than in the full-term babies (62.5 percent). Full-term babies had a higher incidence of ventral developmental midline defects representing abnormalities in closure of the neural tube (precursor of the brain in the fetus), and they had fewer prenatal complications. The premature babies had a higher incidence of prenatal complications with resulting encephaloclastic lesions, indicating the residue of a destructive brain lesion. Four of the 12 babies had regression of retinopathy of prematurity, suggesting that inadequate blood supply may have been a contributing factor. It is suggested that all children with bilateral optic nerve hypoplasia receive a CT scan. Referral to a pediatrician should be made for assessment of other abnormalities. (Consumer Summary produced by Reliance Medical Information, Inc.)

* Biliary papillomatosis is a rare entity characterized by multiple papillary adenomas involving extensive areas of the biliary tract with a great potential for recurrence and malignant transformation. It has been reported in association with Caroli disease and a choledochal cyst. We report herein a case of malignant intrahepatic biliary papillomatosis associated with cirrhosis secondary to hepatitis C. To the best of our knowledge, this is the first report of this association., Biliary papillomatosis is a rare pathologic condition characterized by multiple papillary lesions of the intrahepatic or extrahepatic biliary tree. Only approximately 50 cases have been described in the literature, mainly [...]

Phantom limbs are traditionally conceptualized as the phenomenal persistence of a body part after deafferentation. Previous clinical observations of subjects with phantoms of congenitally absent limbs are not compatible with this view, but, in the absence of experimental work, the neural basis of such 'aplasic phantoms' has remained enigmatic. In this paper, we report a series of behavioral, imaging, and neurophysiological experiments with a university-educated woman born without forearms and legs, who experiences vivid phantom sensations of all four limbs. Visuokinesthetic integration of tachistoscopically presented drawings of hands and feet indicated an intact somatic representation of these body parts. Functional magnetic resonance imaging of phantom hand movements showed no activation of primary sensorimotor areas, but of premotor and parietal cortex bilaterally. Movements of the existing upper arms produced activation expanding into the hand territories deprived of afferences and efferences. Transcranial magnetic stimulation of the sensorimotor cortex consistently elicited phantom sensations in the contralateral fingers and hand. In addition, premotor and parietal stimulation evoked similar phantom sensations, albeit in the absence of motor evoked potentials in the stump. These data indicate that body parts that have never been physically developed can be represented in sensory and motor cortical areas. Both genetic and epigenetic factors, such as the habitual observation of other people moving their limbs, may contribute to the conscious experience of aplasic phantoms.