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The failure of mature mammalian central nervous system axons to regenerate after transection is usually attributed to influences of the extraneuronal milieu.Using explant cocultures of retina and midbrain tectum from hamsters, we have found evidence that these influences account for failure of regrowth ofonly a small minority of retinal axons. For most of the axons, there is a programmed loss of ability to elongate in the central nervous system. We show that there is a precipitous decline in the ability of retinal axons to reinnervate tectal targets when the retina is derived from pups on or after postnatal day 2, even when the target is embryonic. By contrast, embryonic retinal axons can regrow into tectum of any age, overcoming growth-inhibiting influences of glial factors.The rate and extent of axonal growth are influenced by intrinsic properties of individual cells (1, 2) as well as by the substrate through which the axons must navigate (3). During the last decade many studies have focused on the involvement of the extraneuronal milieu in the failure of maturing central nervous system (CNS) axons to regrow over long distances. David and Aguayo (4), utilizing peripheral nerve grafts implanted in the CNS, and Schnell and Schwab (5), applying antibodies to neutralize the effects of oligodendrocyteassociated inhibitory proteins, have shown that some axotomized neurons can be induced to reextend their axons for considerable distances. Regenerating axons from the axotomized retinal ganglion cells (RGCs) extended along the entire length of peripheral nerve grafts, and some penetrated the superior colliculus (SC) up to 500 ,um from the end of the graft. A common interpretation of these findings is that, given the appropriate environment, all neurons should be able to regenerate their exons. However, despite the impressive regrowth of cut axons documented in these studies, the regenerative capacity is expressed by a limited population of neurons (5-9): many transected axons do not regrow into the peripheral nerve graft or regenerate through an area where glial cell inhibitory proteins are neutralized with antibodies.To reexamine the problem of regenerative failure, we have used the primary visual system of the developing hamster as a model, employing organotypic explant cocultures of retina and tectum. This paradigm enables independent variation of the developmental stage of each tissue and allows us to separate the contributions of source and target tissue in influencing the extent of axonal regrowth and target reinnervation.During hamster development, RGC axons leave the eye by embryonic day 10 (E10) and reach the rostral edge of the SC by E14 [day of mating = EO, and day of birth = E16 = postnatal day 0 (PO)]. The axons grow rapidly during this early stage of elongation, maintaining a simple, unbranched morphology as they invade the tectum. At about PO, they shift into a second mode of growth, referred to as the arborization mode, as they begin to emit collateral branches and to elaborate terminal ramific...

DNA methylation is an epigenetic mechanism involved in gene regulation and implicated in the functioning of the nervous system. The de novo DNA methyltransferase Dnmt3a is expressed in neurons, but its specific role has not been clarified. Dnmt3a is activated around embryonic day 10.5 in mouse neuronal precursor cells and remains active in postmitotic neurons in the adult. We assessed the role of neuronal Dnmt3a by conditional gene targeting. Mice lacking functional Dnmt3a in the nervous system were born healthy, but degenerated in adulthood and died prematurely. Mutant mice were hypoactive, walked abnormally, and underperformed on tests of neuromuscular function and motor coordination. Loss of Dnmt3a also led to fewer motor neurons in the hypoglossal nucleus and more fragmented endplates in neuromuscular junctions of the diaphragm muscle. Our results implicate a role for Dnmt3a in the neuromuscular control of motor movement.

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The rodent trigeminal system is characterized by the punctate organization of its afferents and neurons that replicate the distribution of mystacial vibrissae and sinus hairs on the snout. We have examined the development of topographic equivalence between the sensory periphery on the snout and the brainstem trigeminal nuclei in rats. Lipophilic tracers Dil (1,1'-dioctodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) and DiA [4-(4-dihexadecylaminostyryl)-N-methylpyridinium iodide] were used to label trigeminal ganglion cells and their processes differentially from discrete regions of the presumptive vibrissa field in fixed embryos. Our results show that trigeminal ganglion cell processes are spatially ordered as they reach their peripheral and central targets on embryonic day 12 (E12). Peripheral processes of dorsomedially situated ganglion cells course dorsally toward the presumptive vibrissa field, and those of ventrolaterally situated ganglion cells project ventrally. On E13, the central processes of dorsomedially situated ganglion cells enter the brainstem medially whereas those of ventrolaterally situated ganglion cells enter laterally. This spatial order of trigeminal ganglion cell processes precedes the emergence of vibrissa rows in the periphery and the differentiation of brainstem trigeminal nuclei. Thus, the subsequent transfer of the vibrissa-related pattern to the brainstem trigeminal nuclei occurs along a preexisting, spatially aligned bridge formed by the trigeminal ganglion cells.

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In the present study we compare the formation of vibrissa-related patterns by thalamocortical afferents from the ventrobasal (VB) nucleus to that by raphe-cortical, serotonergic afferents from the raphe nuclei. In opposite hemispheres of the same brain, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil) labeling of VB afferents and serotonin (5-HT) immunohistochemistry reveal that the pattern of vibrissa-specific patches is first exhibited by thalamocortical axons in barrel field cortex. Shortly thereafter, 5-HT axons form patches in the same locations as the dense concentrations of VB afferents. To assess a possible role of 5-HT afferents in the specification of barrel field cortex, neonatal rat pups were administered p-chloroamphetamine (PCA), a selective 5-HT neurotoxin. The formation of vibrissa-related patterns by thalamocortical and serotonergic afferents was compared in normal and PCA-treated rat pups at various developmental stages. PCA treatment led to a significant decrease in the number of serotonergic axons in barrel field cortex. Despite this decrease, VB afferents segregated in patches over individual barrels. However, a delay in the emergence of the thalamocortical pattern was noted in toxin-treated animals. We conclude that PCA treatment does not prevent formation of a vibrissa-specific pattern by thalamocortical afferents, and discuss the possibility that the 5-HT axons may play a trophic role in the maturation of VB afferents.