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During development of neuronal networks they are critical for the first step of circuit formation, transducing signals required for axon pathfinding. Surprisingly, the spatial and temporal cAMP and calcium codes used by axon guidance molecules are unknown. Here, we identify characteristics of cAMP and calcium transients generated in growth cones during Netrindependent axon guidance. In contrast, activation of DCC in growth cone centers leads to a transient calcium-dependent cAMP increase and a sustained increase in frequency of calcium transients. We show that filopodial cAMP transients regulate spinal axon guidance in vitro and commissural axon pathfinding in vivo.

These growth cone codes provide a basis for selective activation of specific downstream effectors. It is one of the largest collections of developing human brains. The collection serves as a key resource for many focused research projects and has led to several seminal contributions on mammalian cortical development, such as the discovery of the transient fetal subplate zone and of early bilaminar synaptogenesis in the embryonic and fetal human cerebral cortex, and the first description of growing afferent pathways in the human fetal telencephalon.

The Zagreb Collection also serves as a core resource for ever-growing networks of international collaboration and represents the starting point for many young investigators who now pursue independent research careers at leading international institutions. The Zagreb Collection, however, remains underexploited owing to a lack of adequate funding in Croatia.

Funding could establish an online catalog of the collection and modern virtual microscopy scanning methods to make the collection internationally more accessible.

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The development of different brain regions involves the coordinated control of proliferation and cell fate specification along and across the neuraxis. Here, we identify Plxdc2 as a novel regulator of these processes, using in ovo electroporation and in vitro cultures of mammalian cells. Plxdc2 is a type I transmembrane protein with some homology to nidogen and to plexins. It is expressed in a highly discrete and dynamic pattern in the developing nervous system, with prominent expression in various patterning centres.

In the chick neural tube, where Plxdc2 expression parallels that seen in the mouse, misexpression of Plxdc2 increases proliferation and alters patterns of neurogenesis, resulting in neural tube thickening at early stages. Expression of the Plxdc2 extracellular domain alone, which can be cleaved and shed in vivo, is sufficient for this activity, demonstrating a cell non-autonomous function.

Induction of proliferation is also observed in cultured embryonic neuroepithelial cells ENCs derived from E9. These experiments uncover a direct molecular activity of Plxdc2 in the control of proliferation, of relevance in understanding the role of this protein in various cancers, where its expression has been shown to be altered. They also implicate Plxdc2 as a novel component of the network of signalling molecules known to coordinate proliferation and differentiation in the developing nervous system. Plxdc2 transmembrane protein Plexin domain-containing 2. Molecular Patterning "The midbrain-hindbrain boundary MHB , which expresses Wnt1 and Fgf8, is one of several local signalling centres in the neuroepithelium which refines AP specification of the brain.

DV patterning is influenced by the floor plate, which expresses ventralising factors including sonic hedgehog Shh and nodal and the roof plate at the dorsal midline, which expresses members of the BMP and Wnt families. Differential dorsal and ventral growth of the brain is also co-ordinated via a signalling cascade of Shh, FGF and Wnt activity. Int J Dev Neurosci. Epub Jun In order to quantify human brain development in vivo, high resolution magnetic resonance images of normal subjects from infancy to young adulthood were studied age range 3 months years, 71 males, 87 females.

Data were analysed using algorithms based on voxel-based morphometry VBM an objective whole brain processing technique to generate global volume measures of whole brain, grey matter GM and white matter GM. Gender-specific development of WM and GM volumes is characterised using a piecewise polynomial growth curve model to account for the non-linear nature of human brain development, implemented using Markov chain Monte Carlo simulation.

The statistical method employed in this study proved to be successful and robust in the characterisation of brain development. The resulting growth curve parameter estimates lead to the following observations: total brain volume is demonstrated to undergo an initial rapid spurt. The total GM volume peaks during childhood and decreases thereafter, whereas total WM volume increases up to young adulthood. Relative to brain size, GM decreases and WM increases markedly over this age range in a non-linear manner, resulting in an increasing WM-to-GM ratio over much of the observed age range.

In addition, significant gender differences are found. In general, brain volume and total white and grey matter volume are larger in males than in females, with a time-dependent difference over the age range studied. Over part of the observed age range females tend to have more GM volume relative to brain size and lower WM-to-GM ratio than males. The presented findings should be taken into account when investigating physiological and pathological changes during brain development. The cerebral cortex, cerebral WM, caudate, putamen, pallidum, accumbens area, hippocampus, amygdala, thalamus, brainstem, cerebellar GM, cerebellar WM, lateral ventricles, inferior lateral ventricles, third ventricle, and fourth ventricle were studied.

The cerebral cortex was further analyzed in terms of lobar thickness and surface area. The results revealed substantial heterogeneity in developmental trajectories. GM decreased nonlinearly in the cerebral cortex and linearly in the caudate, putamen, pallidum, accumbens, and cerebellar GM, whereas the amygdala and hippocampus showed slight, nonlinear increases in GM volume.

WM increased nonlinearly in both the cerebrum and cerebellum, with an earlier maturation in cerebellar WM. In addition to similarities in developmental trajectories within subcortical regions, our results also point to differences between structures within the same regions: among the basal ganglia, the caudate showed a weaker relationship with age than the putamen and pallidum, and in the cerebellum, differences were found between GM and WM development.

These results emphasize the importance of studying a wide range of structural variables in the same sample, for a broader understanding of brain developmental principles. The transcription factors Emx2 and Pax6 are expressed in the proliferating zones of the developing rodent neocortex, and gradients of expression interact in specifying caudal and rostral identities. Pax6 is also involved in corticoneurogenesis, being expressed by radial glial progenitors that give rise to cells that also sequentially express Tbr2, NeuroD and Tbr1, genes temporally downstream of Pax6.

However, gradients of expression were similar to that of the rodent at all ages studied. At 8 PCW, PAX6 was highly expressed rostrally but less so caudally, as has been seen in the rodent, however this gradient disappeared early in corticogenesis, by 9 PCW.

These data support recent reports that EMX2 but not PAX6 is more directly involved in arealization, highlighting that analysis of human development allows better spatio-temporal resolution than studies in rodents. J Neurosci. Analyzing the gene expression patterns that underlie these changes and interpreting their significance depends on identifying the anatomical structures to which they map and following these patterns in developing 3D structures over time. The difficulty of this task greatly increases as more gene expression patterns are added, particularly in organs with complex 3D structures such as the brain.

Optical Projection Tomography OPT is a new technology which has been developed for rapidly generating digital 3D models of intact specimens. We have assessed the resolution of unstained neuronal structures within a Carnegie Stage CS 17 OPT model and tested its use as a framework onto which anatomical structures can be defined and gene expression data mapped. Despite the 3D models being of unstained tissue, peripheral nervous system structures from the trigeminal ganglion approximately microm by approximately microm to the rootlets of cranial nerve XII approximately 20 microm in diameter were clearly identifiable, as were structures in the developing neural tube such as the zona limitans intrathalamica core is approximately 30 microm thick.

Fourteen anatomical domains have been identified and visualised within the CS17 model. Two 3D gene expression domains, known to be defined by Pax6 expression in the mouse, were clearly visible when PAX6 data from 2D sections were mapped to the CS17 model. The feasibility of applying the OPT technology to all stages from CS12 to CS23, which encompasses the major period of organogenesis for the human developing central nervous system, was successfully demonstrated.

The OPT models and accompanying technologies for manipulating them provide a powerful approach to visualising and analysing gene expression and morphology during early human brain development. Serial sections of human embryos from Carnegie stages were investigated, and 85 graphic reconstructions were prepared.

It is proposed that neuromeres be defined as morphologically identifiable transverse subdivisions perpendicular to the longitudinal axis of the embryonic brain and extending onto both sides of the body. It is proposed further that primary neuromeres be redefined as the early-appearing larger divisions of the open neural folds, and secondary neuromeres as the smaller subdivisions that are found both before and after closure of the neural tube. In the light of these definitions, 6 primary neuromeres can be detected in the human brain at stage 9, and a maximum of 16 secondary neuromeres at stage The relationships of the 8 rhombomeres to the associated neural crest, as well as to the pharyngeal arches and the exits of the cranial nerves, are tabulated.

Rhombomere 8 Rh. Hence, it is suggested that Rh. The synencephalon, parencephalon, and isthmic neuromere can be distinguished in stage In stage 14, rostral and caudal portions of the parencephalon are recognizable, and the full complement of 16 neuromeres is now present. The medial ventricular eminence appears in the diencephalon D1.

A longitudinal organisation begins to be superimposed on the neuromeres, as now indicated by the appearance of the hypothalamic cell cord. This continues in stage 15, when the hypothalamic sulcus develops. That groove, however, is not continuous with the sulcus limitans. In the diencephalon, five longitudinal zones can be discerned. In stage 16, fibre tracts, such as the habenulo-interpeduncular fasciculus retroflexus and the tract of the posterior commissure, outline the boundaries of the synencephalon.

In stage 17, the tract of the zona limitans intrathalamica along the marginal ridge in the parencephalon is an important landmark. This is the last stage in which all the neuromeres can be distinguished. The number and identity of the neuromeres in the human brain, their precise sequence of appearance, and the stages at which they appear are here clarified for the first time. The results of various studies of domains of gene expression indicate that, although in some instances such territories follow the morphological neuromeres, in others they may cross interneuromeric boundaries.

It is concluded that the precise morphological study of neuromeres in any given species is necessary for correlative investigations of gene expression. The neural groove and folds are first seen during stage 8 about 18 postovulatory days. Two days later stage 9 the three main divisions of the brain, which are not cerebral vesicles, can be distinguished while the neural groove is still completely open. Two days later stage 10 the neural folds begin to fuse near the junction between brain and spinal cord, when neural crest cells are arising mainly from the neural ectoderm.

The rostral or cephalic neuropore closes within a few hours during stage 11 about 24 days. The closure is bidirectional; it takes place from the dorsal and terminal lips and may occur in several areas simultaneously. The two lips, however, behave differently. The caudal neuropore takes a day to close during stage 12 about 26 days and the level of final closure is approximately at future somitic pair 31, which corresponds to the level of sacral vertebra 2.

At stage 13 4 weeks the neural tube is normally completely closed. Secondary neurulation, which begins at stage 12, is the differentiation of the caudal part of the neural tube from the caudal eminence or end-bud without the intermediate phase of a neural plate. Navigation Main page. Site map. The aim of this investigation is threefold: a to determine the time of origin of neurons of the rat cranial nerve ganglia; b to reexamine the embryonic development of the cranial nerve ganglia in the light ofthese dating results; and c to attempt to relate the chronology of these peripheral events to developmental events in those nuclei of the medulla that are intimately associated with the cranial nerve ganglia.

Although thymidine-radiography has been used for over 2 decades to investigate the time of origin of neurons, most of these studies dealt with central nervous struc- tures The aim of this investigation is threefold: a to determine the time of origin of neurons of the rat cranial nerve ganglia; b to reexamine the embr The Development of the Rat Spinal Cord.

Atlas of Human Central Nervous System Development -5 Volume Set

The study of the development of the spinal cord has a relatively long history. The spinal cord was singled out as a favorable site when cytological techniques were first applied to the study of the embryonic development of the nervous system. Bidder and Kupffer , using the new procedure of hardening nerve tissue with chromic acid Hannover , made an investigation of spinal cord development in fetal sheep.

They reported that the cellular central mass of the spinal cord develops before its fibrous envelope, deducing from this that the fibers of the white matter of the embryonic The spinal cord was singled out as a favorable site when cytological te The Development of the Rat Hypothalamus. The hypothalamus is a vitally important component of the vertebrate nervous system, being involved in the regulation of the pituitary gland, the autonomic nervous system, and the central and peripheral motor systems; and implicated in such functions as reproduction, feeding, drinking, aggression, vigilance, and some other not clearly understood motivational processes.

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