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Trisomy 19 (Ts19), the only murine trisomy compatible with survival beyond birth, allows systematic studies on the effect of an additional chromosome upon postnatal development. In this review, developmental consequences of murine Ts19 are presented. In Ts19 mice, viability is limited to a few weeks postpartum. Body weight is markedly reduced. The occurrence of malformations of the cardiovascular, skeletal and central nervous systems depends on the parental genetic background. In all organ systems examined, development is delayed by 1-2 days. Ts19 hematopoietic cells exhibit the same survival rate in lethally irradiated hosts as controls. In the CNS, morphological and morphometric studies fail to detect cytoarchitectonic abnormalities: the orderly pattern of development is not disturbed in the visual cortex, cerebellum, locus coeruleus (LC), optic nerve and retina; but neurogenesis, gliogenesis, myelination and invasion of blood vessels are each delayed by 1-2 days. In addition, size and cell number of different brain regions are reduced to a variable degree: the telencephalon and the cerebellar vermis are markedly hypoplastic, whereas the LC, the optic nerve and the retina are hardly reduced in size. Choline acetyltransferase activity is selectively reduced in the Ts19 telencephalon, whereas the activity of the marker enzyme of the GABAergic system is decreased in all brain regions examined. In behavioral tests, visual capacities and orientation ability of Ts19 mice develop with a 2-day delay, while motor coordination is more severely retarded; there is no response to auditory stimulation. Fetal Ts19 ovaries show excessive oocyte degeneration. Development of the testes is only disturbed postnatally: differentiation of gonocytes to A spermatogonia and formation of B spermatogonia are severely disrupted, resulting in a striking reduction in germ cell number and a predominance of Sertoli cells. Histopathological changes exhibit marked intra- and interindividual variations. In addition, growth and lumen formation are impaired in the seminiferous tubules. The proliferative capacity of cultured Ts19 cells is not altered. The activities of glutamate oxaloacetate transaminase-1 and phosphoglycerate mutase-1 are increased by 50%, compatible with a gene dosage effect of these two enzymes. Ganglioside composition is altered in the Ts19 liver, but not in the brain, spleen and heart. Two-dimensional protein patterns show both chromosome-specific and chromosome-nonspecific changes, their frequency being far lower than expected from the number of proteins coded on chromosome 19. Possible pathogenetic mechanisms are discussed.

The development of the visual cortex was studied in 30 Trisomy 19 (Ts19) mice aged 1-16 days postpartum and their euploid littermates. Morphogenesis of the Ts19 visual cortex, though delayed in development, followed the regular sequence observed in control littermates. Early morphogenetic events, such as obliteration of the ventricular lumen, disappearance of the ventricular zone, formation of a visible apical dendrite, as well as disappearance of both migrating neurons and the columnar organization of bipolar preneurons were delayed by 1 day; maturation steps occurring later such as appearance and disappearance of perikaryal basophilia were delayed by 2 days. Myelination of the white matter was similarly retarded by 2 days. The fronto-occipital length of the cerebral hemispheres and the thickness of the visual cortex were decreased by about 20%, consistent with a hypoplasia of the Ts19 neocortex. Unlike in the cerebral cortex of human Ts21, morphometric analysis of the visual cortex of Ts19 mice did not give any indication of a selective deficit in a particular neuron population; the increased cell density and the reduced nuclear volume observed during early postnatal development are attributable to a maturational delay. The relevance of these results with respect to the mechanisms underlying neuropathological alterations in human Ts21 is discussed.

The development of the folial pattern was studied in the cerebellar vermis of 32 trisomy 19 (Ts19) mice aged 1-16 days postpartum and their euploid littermates. In the Ts19 cerebellum, fissures were formed in the regular sequence observed in control littermates, but their appearance was delayed by about 2 days. Fissure number increased until day 6 in euploid controls and in Ts19 mice, remaining constant thereafter. In Ts19 cerebella, fissure number and fissure depth were reduced significantly; there were 30% fewer Purkinje cells and the cross-sectional areas of the external germinal layer and of the total cerebellar vermis were decreased, reflecting a permanent hypoplasia. Both in Ts19 and control mice, a temporal and quantitative relationship was observed between fissure formation and the expansion of the external germinal layer, whereas the increase in fissure depth was found to correlate with the growth of the whole cerebellar vermis. Determination of the surface folding index revealed that only during fissure formation, the expansion of the cerebellar surface exceeded that of the cerebellar volume. The present study does not give any indication that foliation and histogenesis of the cerebellum are differentially affected by trisomy.

To study the effect of trisomy upon a brain region that is generated very early during development, the locus coeruleus (LC) has been examined morphologically and morphometrically in 23 Trisomy 19 (Ts19) mice and their chromosomally balanced control littermates aged 2-18 days postpartum. Gross morphological alterations of the Ts19 LC could neither be observed by light nor by electron microscopy. The LC was properly located. Ultrastructural features indicating increasing protein synthesis such as nucleolus-like bodies and a rise in the amount of granular endoplasmic reticulum and in the size of the nucleoli have been observed both in Ts19 and control mice. Maturation of the LC was delayed in Ts19. Morphometric studies on the volume, cell number, and cell density revealed that, apart from a 2-day delay in development, the Ts19 LC was of normal size. The present study supports the observation that the noradrenergic system is not affected in the Ts19 CNS. Taking into account that the cerebellum of Ts19 mice is markedly hypoplastic, the results indicate a differential pathogenic effect of trisomy upon different neural systems.

The ganglioside composition of the cerebrum, cerebellum, brainstem, liver, heart, and spleen was analyzed quantitatively in trisomy 19 (Ts19) mice aged 4 to 12 days postpartum. The developmental profiles of cerebral gangliosides were similar in Ts19 mice and control littermates: Total ganglioside-sialic acid as well as the proportions of the individual gangliosides GD1a and GM1 increased with age, while the percentages of GQ1b and GT1b decreased during development. Both the accretion of the total ganglioside content and the development of the individual ganglioside fractions were delayed by 2-3 days in the Ts19 telencephalon. Likewise, the shift from the b- to the a-pathway of ganglioside synthesis was retarded. Ganglioside development was equally delayed in the cerebellum and the brainstem of Ts19 mice. Since in Ts19 mice, morphogenesis of several brain regions is similarly delayed by 2 days, these results confirm the usefulness of gangliosides as biochemical markers for brain maturation. In contrast to brain gangliosides, the ganglioside composition of the Ts19 livers was clearly distinguished from that of control livers. Total ganglioside-bound sialic acid was increased by 35-50% in Ts19 livers. This elevation in ganglioside content not explicable by a simple delay in development was mainly due to an increase in GD3 and fraction 2, which is likely to contain GD1a and GD1b. In contrast, GM2 which increased considerably with age in control mice persisted on a low level in Ts19 livers. Comparable alterations of the ganglioside pattern were neither observed in the spleen nor in the heart of Ts19 mice. The data presented give additional evidence that ganglioside synthesis in the liver is under a different regulation mechanism than that in the brain, heart, and spleen.

Trisomy 19 (ts19) of the mouse permits detailed studies on the influence of an extra autosome upon the postnatal development of the central nervous system. To examine gliogenesis and myelinogenesis, the optic nerves of 19 ts19 pugs aged 1-15 days have been examined by light and electron microscopy and compared to those of litter-mate controls. Differentiation of astrocytes and oligodendrocytes, myelinogenesis as well as the opening of the eyes are each delayed by about 2 days. Myelin sheaths are normally structured in ts19. There is a decrease in the percentage of myelinated fibres. The cross-sectional area of the ts19 optic nerve is reduced. The fibre density, which decreases with age both in ts19 and control mice, is higher in ts19 mice. Both with ts19 and control animals, the distribution of fibre diameters of myelinated axons overlaps with that of promyelinated and unmyelinated fibres, but myelinated axons cannot be observed below a diameter of 0.3 micron, and unmyelinated axons are always smaller than 1 micron. The mean diameter of promyelinated axons is identical in ts19 and control animals. Myelination is therefore not severely disturbed in the ts19 optic nerve. As retinal differentiation in ts19 is delayed by 2 days as well, reports on an asynchronous development of neurons and myelin sheaths cannot be confirmed for the visual system.

To investigate the development of the retinal layers, the eyes of mice with trisomy 19 have been examined by light microscopy between the 2nd and 15th postnatal day. The diameter of the eye, thickness of the entire retina and both relative thickness and nuclear density of each of the retinal layers have been measured and compared to those of chromosomally balanced control animals. Malformations of the eye, alterations of cell morphology or disturbed lamination can not be observed. Retinal differentiation of trisomy 19 mice is delayed by approximately two days. The development of all cellular constituents, i.e., of both neuroectodermal and mesenchymal origin, is retarded accordingly. The eyes of trisomy 19 mice are of reduced size. The relative thickness of each retinal layer follows a normal growth pattern; there is no indication for a selective impairment of the development of one particular layer. With the exception of the ganglion cell layer, nuclear densities of each retinal layer do not differ from those of control mice. The comparison of nuclear densities in the ganglion cell layer suggests that in trisomy 19 mice fewer postmitotic cells differentiate into mature retinal cells.

Retinal development of trisomy 19 (Ts19) mice has been studied by microscopy from postnatal day 2 (PD 2) to PD 15. Gross malformations of the eye or alterations of the cellular arrangement are not detectable; retinal differentiation follows the regular pattern observed in chromosomally balanced control littermates. At all stages examined, the development of the retina in Ts19 lags approximately 2 days behind littermate controls. The maturation of all cellular constituents examined is retarded to the same degree. Appearance of the outer plexiform layer, cessation of mitotic activity, penetration of blood vessels in the nerve fiber layer and in the outer plexiform layer, differentiation of the inner granular layer and receptor formation are each delayed about two days. On a cellular level, there is no indication for an asynchronous development in the retina of Ts19. In addition to the retarded maturation, the diameters of the eyes are reduced in Ts19 mice.