Developmental genetics

Of particular concern to the human geneticist are the effects of genetic abnormalities on development. To gain an understanding of these effects it is necessary to engage in a reciprocal process of using knowledge of normal developmental events to elucidate the mechanisms operative in abnormal situations and then of using what is learned about these abnormal situations to expand our understanding of the normal. True developmental genes have not been described in man, although it is likely that they exist, but many developmental abnormalities are ascribable to mutations in genes coding for enzymes and structural proteins. Some of these even produce multiple malformation syndromes with dysmorphic features. These situations provide a precedent for asserting that not only monogenic developmental abnormalities, but also abnormalities resulting from chromosome imbalance must ultimately be explicable in molecular terms. However, the major problem confronted by the investigator interested in the pathogenesis of any of the chromosome anomaly syndromes is to understand how the presence of an extra set of normal genes or the loss of one of two sets of genes has an adverse effect on development. Several molecular mechanisms for which limited precedents exist may be considered on theoretical grounds. Because of the difficulties in studying developmental disorders in man, a variety of experimental systems have been employed. Particularly useful has been the mouse, which provides models for both monogenic and aneuploidy produced abnormalities of development. An example of the former is the mutation oligosyndactylism which in the heterozygous state causes oligosyndactyly and in the homozygous state causes early embryonic mitotic arrest. All whole arm trisomies and monosomies of the mouse can be produced experimentally, and of special interest is mouse trisomy 16 which has been developed as an animal model of human trisomy 21 (Down syndrome). In the long run, the most direct approach to elucidating the genetic problems of human development will involve not only the study of man himself but also of the appropriate experimental models in other species.     

Norzooanemonin in the hydroidTubularia larynx

Summary The hydrochloride of 1,3-dimethyl imidazole-4-carboxylic acid (norzooanemonin), has been isolated from the hydroidTubularia larynx and its structure determined by X-ray analysis.This investigation was supported by grant No. HD-04543 from the National Institutes of Child Health and Human Development. One of us (RLM) also wishes to thank the National Institutes of Health for a Career Development award No. HD-19931.     

Growth-modulating serum tripeptide is glycyl-histidyl-lysine

Summary The structure of a growth-modulating tripeptide from human serum and plasma has been determined to be H-glycyl-histidyl-lysine-OH.Acknowledgment. This work was supported by grants from the U.S. Public Health Service (HD-03148 and P17AM 18520) and from the National Cancer Institute (NO-1-CB53868).     

Seasonal changes in the uptake capacity of the suprachiasmatic nucleus for3H-serotonin

Summary The suprachiasmatic nucleus, a hypothalamic center important in mediation of circadian and estrous cycles, is shown in adult rats to have seasonal changes in its uptake capacity in vitro for³H-serotonin.Supported in part by grants from the National Institute of Mental Health (MH-25091), the National Institute of Health (HD-10263, HD-03352, 5-T01-HD00104-10), USPHS, and the Ford Foundation (grant No. 630-0505 B, C).     

Overexpression of copper-zinc superoxide dismutase in trisomy 21

Down's syndrome (DS), the most frequent of congenital birth defects, results from the trisomy of chromosome 21 in all cells of affected patients. This disease is characterized by developmental anomalies, mental retardation and features of rapid aging, particularly in the brain, where the occurrence of Alzheimer's disease is observed in trisomy 21 patients over the age of 35. Copper-zinc superoxide dismutase (CuZnSOD) is one of the proteins encoded by chromosome 21 (21q22.1). As a consequence of gene dosage excess, CuZnSOD activity is increased by 50% in all DS tissues. This work reports the SOD activity of a population of DS patients with complete trisomy 21, partial trisomy 21, translocations and mosaicism, in order to confirm the gene dosage effect of SOD on the clinical features of DS, and to help to establish which is the critical region of chromosome 21 in DS. CuZnSOD was measured in red blood cells using the Minami and Yoshikawa method. In the population with complete trisomy 21, SOD activity was increased by 42%; in the population with partial trisomy 21, translocations and mosaicism, SOD activity was normal. In the population diagnosed as DS, but not karyotyped, SOD activity was increased by 28%. No differences between sexes or among ages were found. We conclude that the 21q22.1 segment is not the critical region responsible for DS, as we have found normal SOD activity in patients with the clinical features of DS.     

Estrogen binds to hypothalamic nuclei of androgen-insensitive (tfm) rats

Summary Androgen-insensitive (tfm) rats possess a nuclear-estrogen binding system in the brain that is similar to that of wild-type control males. In these mutant rats, radiolabeled estradiol was bound predominantly to hypothalamic nuclei and this binding was of limited capacity.This research was supported by grants Nos HD-13957 and HD-14726 from the National Institute of Child Health and Human Development.     

Physical growth and brain development of captive-bred male and female squirrel monkeys,Saimiri sciureus

Summary The physical growth and brain development of the captive bred male and female squirrel monkeys have shown that the male grows at a significantly faster rate with respect to these parameters in the postnatal life, starting from preweaning stage as compared to the female infant. During the prenatal life the male and the female fetuses grow at similar rates and show comparable brain development as indicated by its weight.Acknowledgments. This work was supported by USPHS Grants RR-00165 and HD-06087 from National Institutes of Health. The technical assistance of Mrs Judie Wells is greatly appreciated.     

Adrenal dopamine-β-hydroxylase activity: 24-hour rhythmicity and evidence for pineal control

Summary Adrenal medullary dopamine--hydroxylase activity was found in male rats to have a 24-hour rhythm, with an approximately 6-fold increase at about the time of the onset of darkness. This nocturnal rise in enzyme activity did not occur when lights were kept on, nor did it occur in animals that had been pinealectomized.Supported in part by grants from the Ford Foundation (No. 630-05050A), National Institutes of Health (No. HD-03352) and National Institute of Mental Health (No. MH-25019) USPHS.     

Polypeptides of the lens fibre cell intracellular matrix

Summary The cytoskeletal proteins of the vertebrate lens fibre cell comprise polypeptides ranging in mol.wt from 43,000 to 250,000 daltons. The main intermediate filament polypeptide of the pickerel, Northern frog, chick, bovine, and human lens has a mol.wt of 54,000 daltons. Peptide analysis revealed that the chick 54,000 dalton protein was more similar to the bovine protein than to the pickerel protein.Supported by grants EY 01417 (H. Maisel) and HD-06390 (J.C. Brown, University of Virginia, Charlottesville) from the National Institutes of Health, U.S.P.H.S.     

Anti-estrogen inhibition of testosterone-stimulated aggression in mice

Summary Testosterone-stimulated intermale aggression in castrated mice can be reversibly inhibited by anti-estrogen administration suggesting that estrogen formation and actions in the brain may be required for testosterone's behavioral actions.Supported by Grant HD-07049 from the National Institutes of Health. The CI-628 was generously provided by Parke, Davis (Ann Arbor, Michigan, USA).     

Lipofuscin accumulation in squirrel monkey spinal cord consequent to protein malnutrition during gestation

Summary The formation of lipofuscin pigment in the anterior horn cells of the cervical spinal cord has shown in the fetuses and neonates under the extrinsic influence of maternal protein deprivation during the gestation period in the squirrel monkeys.Acknowledgments. This work was supported by US PHS grants RR-00165 HD-06087 from National Institute of Health. The technical assistance of Miss Judie Seubert is greatly appreciated.     

Close association of erythrocytes with surface of late mouse blastocysts: SEM analysis

Summary SEM analysis of preimplantation mouse blastocysts reveals closely associated red blood cells on involuted surfaces of trophoblasts, an indication of the capability for initial phases of phagocytosis at an early developmental stage.Acknowledgment. This study was supported by NICHD grant HD-06234 and NIH grant RR-05384. Author for reprint requests.     

Daily melatonin injections inhibit short-day-induced testicular regression in hamsters

Summary Daily injections of melatonin were found to retard testicular regression in hamsters exposed to LD 10:14, if the injections occurred in the morning (i.e., 0.5 h after lights on), but not if they occurred in the afternoon (i.e., 6 h after lights on). These results indicate that appropriately timed injections of melatonin can at least partially block the inhibitory effects of short days on gonadal activity in the photoperiodic hamster.We wish to thank Susan Losee and Susan Stice for excellent technical assistance and Gary Ellis for his comments. This investigation was supported by NIH grants HD-09885, HD 12622 and Research Career Development Award HD-00249 (F. W. T.) from the National Institute of Child Health and Human Development.     

Human adenosine deaminase and chromosome 20

Summary In patients exhibiting in marrow cells deletion of the long arm of chromosome 20, the specific activities of adenosine deaminase in cells of the peripheral blood are normal. This suggests that the gene for adenosine deaminase is not localized to the distal segment of the long arm of this chromosome.This work was supported by Grants from the National Health and Medical Research Council of Australia and the Anti-Cancer Council of Victoria.     

Plasma prolactin levels in fetal sheep

Zusammenfassung Entwicklung und Spezifität eines radioimmunologischen Verfahrens für Schaf-Prolaktin. Zirkulierende Prolaktinmengen wurden in Fetussen bestimmt und vom 110. bis zum 122. Tage bedeutende Prolaktinmengen festgestellt.

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Supported by a grant No. HD-00394 from the National Institutes of Health.     

From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner's syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner's syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed.     

Distribution of tetracycline-73H in subcellular components of normal and tumor tissues of the albino rat

Zusammenfassung Die Verteilung von Tritium-markiertem Tetracyclin (TTC) in subcellulären Fraktionen von normalem und neoplastischem Gewebe wurde untersucht. Der grösste Teil des injizierten TTC wurde in der Mikrosomen-Fraktion (49000g) gefunden. Tumorgewebe wenige Tage nach Transplantation nahm mehr TTC als irgendein anderes der untersuchten Gewebe auf.

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This study has been supported by grants from the National Institute of Child Health and Human Development, No. HD-00451 and the American Medical Association Committee on Research and Education.     

Role of inorganic phosphate in total biliary phosphorus determination

Summary Total phosphorus, inorganic phosphate, and phospholipids were measured in bile of rats and guinea pigs during choleresis and cholestasis produced by taurocholate and taurolithocholate, respectively. Under either experimental condition, total biliary phosphorus concentrations increased significantly in both species, due primarily to an increase in inorganic phosphate. These studies indicate that, if total phosphorus is taken as an estimate of biliary phospholipid concentration, correction for inorganic phosphate is essential under conditions associated with changes in bile secretory function.This work was supported by grant HD-17556 from the National Institute of Child Health and Human Development.     

Effect of histamine on the diameter of skeletal muscle fibers in mice

Résumé Des souris reçurent des injections intrapéritonéales de bichlorure d'histamine. Le diamètre moyen des fibres musculaires s'en trouva nettement réduit et des modifications histologiques furent notées chez les souris traitées.

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Supported by grant HD-00221, National Institutes of Health, U.S. Public Health Service. I wish to gratefully acknowledge the technical assistance of MissF. Vaughan.