A role for mDia, a Rho-regulated actin nucleator, in tangential migration of interneuron precursors.

In brain development, distinct types of migration, radial migration and tangential migration, are shown by excitatory and inhibitory neurons, respectively. Whether these two types of migration operate by similar cellular mechanisms remains unclear. We examined neuronal migration in mice deficient in mDia1 (also known as Diap1) and mDia3 (also known as Diap2), which encode the Rho-regulated actin nucleators mammalian diaphanous homolog 1 (mDia1) and mDia3. mDia deficiency impaired tangential migration of cortical and olfactory inhibitory interneurons, whereas radial migration and consequent layer formation of cortical excitatory neurons were unaffected. mDia-deficient neuroblasts exhibited reduced separation of the centrosome from the nucleus and retarded nuclear translocation. Concomitantly, anterograde F-actin movement and F-actin condensation at the rear, which occur during centrosomal and nuclear movement of wild-type cells, respectively, were impaired in mDia-deficient neuroblasts. Blockade of Rho-associated protein kinase (ROCK), which regulates myosin II, also impaired nuclear translocation. These results suggest that Rho signaling via mDia and ROCK critically regulates nuclear translocation through F-actin dynamics in tangential migration, whereas this mechanism is dispensable in radial migration.

Nolz1 promotes striatal neurogenesis through the regulation of retinoic acid signaling.

BACKGROUND: Nolz1 is a zinc finger transcription factor whose expression is enriched in the lateral ganglionic eminence (LGE), although its function is still unknown. RESULTS: Here we analyze the role of Nolz1 during LGE development. We show that Nolz1 expression is high in proliferating neural progenitor cells (NPCs) of the LGE subventricular zone. In addition, low levels of Nolz1 are detected in the mantle zone, as well as in the adult striatum. Similarly, Nolz1 is highly expressed in proliferating LGE-derived NPC cultures, but its levels rapidly decrease upon cell differentiation, pointing to a role of Nolz1 in the control of NPC proliferation and/or differentiation. In agreement with this hypothesis, we find that Nolz1 over-expression promotes cell cycle exit of NPCs in neurosphere cultures and negatively regulates proliferation in telencephalic organotypic cultures. Within LGE primary cultures, Nolz1 over-expression promotes the acquisition of a neuronal phenotype, since it increases the number of ß-III tubulin (Tuj1)- and microtubule-associated protein (MAP)2-positive neurons, and inhibits astrocyte generation and/or differentiation. Retinoic acid (RA) is one of the most important morphogens involved in striatal neurogenesis, and regulates Nolz1 expression in different systems. Here we show that Nolz1 also responds to this morphogen in E12.5 LGE-derived cell cultures. However, Nolz1 expression is not regulated by RA in E14.5 LGE-derived cell cultures, nor is it affected during LGE development in mouse models that present decreased RA levels. Interestingly, we find that Gsx2, which is necessary for normal RA signaling during LGE development, is also required for Nolz1 expression, which is lost in Gsx2 knockout mice. These findings suggest that Nolz1 might act downstream of Gsx2 to regulate RA-induced neurogenesis. Keeping with this hypothesis, we show that Nolz1 induces the selective expression of the RA receptor (RAR)ß without altering RARα or RARγ. In addition, Nozl1 over-expression increases RA signaling since it stimulates the RA response element. This RA signaling is essential for Nolz1-induced neurogenesis, which is impaired in a RA-free environment or in the presence of a RAR inverse agonist. It has been proposed that Drosophila Gsx2 and Nolz1 homologues could cooperate with the transcriptional co-repressors Groucho-TLE to regulate cell proliferation. In agreement with this view, we show that Nolz1 could act in collaboration with TLE-4, as they are expressed at the same time in NPC cultures and during mouse development. CONCLUSIONS: Nolz1 promotes RA signaling in the LGE, contributing to the striatal neurogenesis during development.

Binocular competition does not regulate retinogeniculate arbor size in fetal monkey.

Binocular interactions play a prominent role in shaping the axonal arbors of geniculocortical fibers and the arbors of Y cells in the retinogeniculate pathway of the fetal cat. Fiber interactions between the two eyes have also been suggested to regulate the formation of retinal projections to the dorsal lateral geniculate nucleus (dlgn) of the fetal monkey, but whether this reflects structural refinements of retinal arbors has not been established. To address this issue, we quantified the morphologic properties of individual fibers in two macaque monkeys at embryonic day (E) 110 and E121 that had an eye removed at E69 and E61, respectively. Fibers were labeled by DiI crystals into the fixed optic tract and were visualized by confocal microscopy. Three measurements were made: the number of branch points within the axon terminal arbor, the total arborization length, and the incidence of axonal side branches on the preterminal axon within the confines of the geniculate. There were no significant differences with respect to these parameters between the prenatal enucleates and normal monkeys of comparable age. This was the case for retinal fibers innervating the magnocellular and the parvocellular segments of the dlgn. The arbors stemming from the remaining eye were widely distributed in the dlgn, with some terminating in territories normally innervated by the other (enucleated) eye. These results lend support to the hypothesis that the expanded projection from the remaining eye to the lateral geniculate nucleus of the prenatally enucleated monkey is due to the maintenance of a contingent of retinal fibers normally eliminated by ganglion cell death.

Development of primary visual projections occurs entirely postnatally in the fat-tailed dunnart, a marsupial mouse, Sminthopsis crassicaudata.

We have examined the development of retinal projections in a diminutive polyprotodont marsupial, the fat-tailed dunnart, Sminthopsis crassicaudata. Here, we document the most immature mammalian visual system at birth described to date. At postnatal day (P) 0, the retinal ganglion cell layer has yet to form, and axons have not entered the optic stalk. By P4, the retinal ganglion cell layer could be distinguished at the posterior pole, and the front of growing axons extended one-third the length of the optic stalk, a distance of approximately 150 microm; a few pioneer growth cones had grown beyond the main axon group but had still to reach the midline. Axons had decussated at the optic chiasm by P10 to penetrate the base of the contralateral optic tract and, by P15, had reached the dorsal lateral geniculate nucleus (dLGN), superior colliculus (SC), and accessory optic system (AOS); ipsilaterally projecting axons matured slightly later. From P20, axons had reached the caudal SC both contralaterally and ipsilaterally and terminated throughout the depth of the retinorecipient layers. After P30, the projections gradually refined. Within the rostral dLGN, segregation into four contralateral and four ipsilateral bands occurred by P50, approximately 5 days after eye opening. The projection to the ipsilateral SC underwent refinement by P50, becoming restricted to its rostral pole, and presented as discrete patches within the stratum opticum. At birth, the dunnart visual system is comparable to early to midembryonic stages [embryonic day (E) 12, E14, E19, E24, and E30, respectively] in the mouse, rat, ferret, cat, and monkey. The extreme immaturity of the neonatal dunnart together with the observation that the entire development of the primary optic pathway occurs postnatally over a protracted period make this marsupial especially valuable for investigating factors that control pathway formation in the early developing mammalian primary visual system.

The effect of spaceflight on retino-hypothalamic tract development.

NASA: Researchers examined the effect of late prenatal exposure to microgravity on the development of the retina, retinohypothalamic tract, geniculo-hypothalamic tract, and suprachiasmatic nucleus. Results indicate an effect on c-fos activity in the intergeniculate leaflet between gestational day 20 and postnatal day 8, suggesting a delay in development of the circadian timing system.^ieng

Synaptogenesis in the occipital cortex of macaque monkey devoid of retinal input from early embryonic stages.

The role of input from the retina on the development of synaptic organization in the primate striate cortex was examined in macaque monkeys enucleated at embryonic (E) day 67 and E59. Both the prenatally operated animals and their age-matched controls were delivered at term (E165) and killed either at 3 months (at the end of the rapid phase of synaptogenesis) or 3 years (at the end of the plateau phase of synaptogenesis). As expected, in the operated animals the striate cortex had a smaller surface area but a normal thickness and complement of layers. The present study revealed that the mean densities of synaptic contacts per unit area and volume of neuropil in the striate cortex of the two operated animals were similar to those of age-matched controls (approximately 30/100 microm2 or 100/100 microm3 of neuropil). Thus, the absence of retinal input via the lateral geniculate nucleus did not affect the schedule and magnitude of synaptogenesis. Likewise, the ratio of symmetrical versus asymmetrical synapses and mean lengths of synaptic junctions were within the normal range of variation in both group of animals. The proportions of synaptic contacts situated on dendritic spines and shafts were also similar in supra- and infragranular cortical layers of normal and enucleated animals. However, the ratio of synapses situated on dendritic spines and shafts in the sublayers IVAB and IVC, which normally become reversed during late adolescence, were not reversed in the enucleates. Therefore, our study indicated that certain parameters of synaptic development, such as the density of contacts per unit volume of neuropil and the proportion of basic types and their size, in the supra- and infragranular layers of the striate cortex develop to an optimal normal level in the absence of both retinae from early embryonic stages. However, in the thalamorecipient sublayers the details of the synaptic circuits such as their localization on dendritic spines or shafts, fail to mature properly in the absence of normal functional input from the periphery.

Prenatal disruption of binocular interactions creates novel lamination in the cat's lateral geniculate nucleus.

The elimination of retinogeniculate afferents from one eye on embryonic day 44 (E44) has pronounced effects on the formation of the cellular laminae in the cat lateral geniculate nucleus (LGN). Only two laminae form: a dorsal, "magnocellular" layer, and a ventral, "parvocellular" layer. Soma size measurements and previously reported patterns of termination of retinogeniculate axons suggest that the dorsal lamina is a coalescence of the normal A-laminae and the dorsal, magnocellular division of layer C, while the ventral layer is a composite of the parvocellular sublamina of layer C and the remaining C-laminae. This is a novel pattern of lamination in the LGN that differs from that found in the normal nucleus, not only in that there are now only two cell layers rather than the normal five, but also in that the interlaminar zone occurs in an abnormal location. This result is markedly different from that observed in other species where interlaminar zones present after early monocular enucleation are a subset of the ones which would normally be present. We suggest that, in the absence of ongoing binocular interactions, interactions between functionally distinct retinal ganglion cell classes from the remaining eye may direct the formation of cell laminae in the LGN, even when such interactions are not normally operative.