The present study is devoted to describing the “logic” implicit in the standard genetic code. Bases are considered as physicochemical entities possessing two essential properties: molecular type and number of Hydrogen bonds involved (bases pairing) in the codon-anticodon specific interactions. It is proposed that the codon structure possesses a dual informative function: on the one hand, it determines its discriminating or non-discriminating character, and on the other hand, it determines a specific amino acid. These two aspects constitute the codon global information. Two different sets of rules are introduced to describe these different phenomena. It is established that, depending on the type of base occupying the second position, only two or three of the six codon properties located at defined positions determine the discriminating or non-discriminating behavior. With regard to the amino acid determining function of the codons for different sets of synonymous (singlets, doublets, triplets, quadruplets, or sextets), the number of informative properties integrating the codon and their typical positions characteristically change. Based on the rules presented here, it can be postulated that a codon can be defined as an asymmetric informative entity, whose global informative capacity results from the spatially organized combination of the six properties assigned by the three bases.

The frontal lobes are one of the most complex brain structures involved in both domain-general and specific functions. The goal of this work was to assess the anatomical and cognitive affectations from a unique case with massive bilateral frontal affectation. We report the case of GC, an eight-year old child with nearly complete affectation of bilateral frontal structures and spared temporal, parietal, occipital, and cerebellar regions. We performed behavioral, neuropsychological, and imaging (MRI, DTI, fMRI) evaluations. Neurological and neuropsychological examinations revealed a mixed pattern of affected (executive control/abstraction capacity) and considerably preserved (consciousness, language, memory, spatial orientation, and socio-emotional) functions. Both structural (DTI) and functional (fMRI) connectivity evidenced abnormal anterior connections of the amygdala and parietal networks. In addition, brain structural connectivity analysis revealed almost complete loss of frontal connections, with atypical temporo-posterior pathways. Similarly, functional connectivity showed an aberrant frontoparietal network and relative preservation of the posterior part of the default mode network and the visual network. We discuss this multilevel pattern of behavioral, structural, and functional connectivity results. With its unique pattern of compromised and preserved structures and functions, this exceptional case offers new constraints and challenges for neurocognitive theories.

A decrease in the concentration of oxygen in the blood and tissues (hypoxia) produces important, sometimes irreversible, damages in the central nervous system (CNS) both during development and also postnatally. The present work aims at analyzing the expression of nerve growth factor (NGF) and p75 and the activation of TrkA in response to an acute normobaric hypoxic event and to evaluate the possible protective role of exogenous NGF. The developing chick optic tectum (OT), a recognized model of corticogenesis, was used as experimental system by means of in vivo and in vitro studies.Based on identification of the period of highest sensitivity of developmental programmed cell death (ED15) we show that hypoxia has a mild but reproducible effect that consist of a temporal increase of cell death 6 h after the end of a hypoxic treatment. Cell death was preceded by a significant early increase in the expression of Nerve Growth Factor (NGF) and its membrane receptor p75. In addition, we found a biphasic response of TrkA activation: a decrease during hypoxia followed by an increase −4 h later- that temporally coincide with the interval of NGF overexpression. To test the NGF - NGF receptors role in hypoxic cell death, we quantified, in primary neuronal cultures derived from ED15 OT, the levels of TrkA activation after an acute hypoxic treatment. A significant decline in the level of TrkA activation was observed during hypoxia followed, 24 h later, by significant cell death. Interestingly, this cell death can be reverted if TrkA inactivation during hypoxia is suppressed by the addition of NGF.Our results suggest that TrkA activation may play an important role in the survival of OT neurons subjected to acute hypoxia. The role of TrkA in neuronal survival after injury may be advantageously used for the generation of neuroprotective strategies to improve prenatal insult outcomes.

The present article summarizes the main events involved in the isthmic organizer and optic tectum determination and analyses how optic tectum patterning is translated, by the organized operation of several specific cell behaviors, into the terminally differentiated optic tectum. The paper proposes that this assembling of temporally/spatially organized cell behaviors could be incorporated into a wider notion of patterning and that, given the asymmetric organization of the developing optic tectum, the notion of "sensitive period" does not capture the whole complexity of midbrain development and the pathogenesis of congenital disorders. The cell behaviors involved in the optic tectum development are organized in time and space by the isthmic organizer. A comprehensive description of the normal optic tectum development, and also its alterations, should consider both domains. Significantly, the identity of each neuronal cohort depends critically on its "time and place of birth". Both parameters must be considered at once to explain how the structural and functional organization of the optic tectum is elaborated. The notion of "patterning" applies only to the early events of the optic tectum development. Besides, the notion of "sensitive period" considers only a temporal domain and disregards the asymmetric organization of the developing optic tectum. The present paper proposes that these notions might be re-defined: (a) a wider meaning of the term patterning and (b) a replacement of the term "sensitive period" by a more precise concept of "sensitive temporal/spatial window".

The central nervous system areas displaying the highest structural and functional complexity correspond to the so called cortices, i.e., concentric alternating neuronal and fibrous layers. Corticogenesis, i.e., the development of the cortical organization, depends on the temporal-spatial organization of several developmental events: (a) the duration of the proliferative phase of the neuroepithelium, (b) the relative duration of symmetric (expansive) versus asymmetric (neuronogenic) sub phases, (c) the spatial organization of each kind of cell division, (e) the time of determination and cell cycle exit and (f) the time of onset of the post-mitotic neuronal migration and (g) the time of onset of the neuronal structural and functional differentiation. The first five events depend on molecular mechanisms that perform a fine tuning of the proliferative activity. Changes in any of them significantly influence the cortical size or volume (tangential expansion and radial thickness), morphology, architecture and also impact on neuritogenesis and synaptogenesis affecting the cortical wiring. This paper integrates information, obtained in several species, on the developmental roles of cell proliferation in the development of the optic tectum (OT) cortex, a multilayered associative area of the dorsal (alar) midbrain. The present review (1) compiles relevant information on the temporal and spatial organization of cell proliferation in different species (fish, amphibians, birds, and mammals), (2) revises the main molecular events involved in the isthmic organizer (IsO) determination and localization, (3) describes how the patterning installed by IsO is translated into spatially organized neural stem cell proliferation (i.e., by means of growth factors, receptors, transcription factors, signaling pathways, etc.) and (4) describes the morpho- and histogenetic effect of a spatially organized cell proliferation in the above mentioned species. A brief section on the OT evolution is also included. This section considers how the differential operation of cell proliferation could explain differences among species.

Background: In the development of the central nervous system (CNS), neuronal migration and neuritogenesis are crucial processes for establishing functional neural circuits. This relies on the regulation exerted by several signaling molecules, which play important roles in axonal growth and guidance. The urokinase‐type plasminogen activator (uPA)—in association with its receptor—triggers extracellular matrix proteolysis and other cellular processes through the activation of intracellular signaling pathways. Even though the uPA‐uPAR complex is well characterized in nonneuronal systems, little is known about its signaling role during CNS development. Results: In response to uPA, neuronal migration and neuritogenesis are promoted in a dose‐dependent manner. After stimulation, uPAR interacts with α5‐ and β1‐integrin subunits, which may constitute an αβ‐heterodimer that acts as a uPA‐uPAR coreceptor favoring the activation of multiple kinases. This interaction may be responsible for the uPA‐promoted phosphorylation of focal adhesion kinase (FAK) and its relocation toward growth cones, triggering cytoskeletal reorganization which, in turn, induces morphological changes related to neuronal migration and neuritogenesis. Conclusions: uPA has a key role during CNS development. In association with its receptor, it orchestrates both proteolytic and nonproteolytic events that govern the proper formation of neural networks. Developmental Dynamics 243:676–689, 2014. © 2014 Wiley Periodicals, Inc.

Background: Cell proliferation plays an important morphogenetic role. This work analyzes the temporal–spatial organization of cell proliferation as an attempt to understand its contribution to the chick optic tectum (OT) morphogenesis. Results: A morphogenetic model based on space-dependent differences in cell proliferation is presented. Step1: a medial zone of high mitotic density (mZHMD) appears at the caudal zone. Step2: the mZHMD expands cephalically forming the dorsal curvature and then duplicates into two bilateral ZHMDs (bZHMD). Step3: the bZHMDs move toward the central region of each hemitectum. Step4: the planar expansion of both bZHMD and a relative decrement in the dorsal midline growth produces a dorsal medial groove separating the tectal hemispheres. Step5: a relative caudal displacement of the bZHMDs produces the OT caudal curvature. Numerical sequences derived from records of mitotic cells spatial coordinates, analyzed as stochastic point processes, show that they correspond to 1/f (β) processes. The spatial organization subsumes deterministic and stochastic components. Conclusions: The deterministic component describes the presence of a long-range influence that installs an asymmetric distribution of cell proliferation, i.e., an asymmetrically located ZHMD that print space-dependent differences onto the tectal corticogenesis. The stochastic component reveals short-range anti-correlations reflecting spatial clusterization and synchronization between neighboring cells. Developmental Dynamics 241:1043–1061, 2012. © 2012 Wiley Periodicals, Inc.

BACKGROUND:Retinotopic projection onto the tectum/colliculus constitutes the most studied model of topographic mapping and Eph receptors and their ligands, the ephrins, are the best characterized molecular system involved in this process. Ephrin-As, expressed in an increasing rostro-caudal gradient in the tectum/colliculus, repel temporal retinal ganglion cell (RGC) axons from the caudal tectum and inhibit their branching posterior to their termination zones. However, there are conflicting data regarding the nature of the second force that guides nasal axons to invade and branch only in the caudal tectum/colliculus. The predominant model postulates that this second force is produced by a decreasing rostro-caudal gradient of EphA7 which repels nasal optic fibers and prevents their branching in the rostral tectum/colliculus. However, as optic fibers invade the tectum/colliculus growing throughout this gradient, this model cannot explain how the axons grow throughout this repellent molecule.METHODOLOGY/PRINCIPAL FINDINGS:By using chicken retinal cultures we showed that EphA3 ectodomain stimulates nasal RGC axon growth in a concentration dependent way. Moreover, we showed that nasal axons choose growing on EphA3-expressing cells and that EphA3 diminishes the density of interstitial filopodia in nasal RGC axons. Accordingly, in vivo EphA3 ectodomain misexpression directs nasal optic fibers toward the caudal tectum preventing their branching in the rostral tectum.CONCLUSIONS:We demonstrated in vitro and in vivo that EphA3 ectodomain (which is expressed in a decreasing rostro-caudal gradient in the tectum) is necessary for topographic mapping by stimulating the nasal axon growth toward the caudal tectum and inhibiting their branching in the rostral tectum. Furthermore, the ability of EphA3 of stimulating axon growth allows understanding how optic fibers invade the tectum growing throughout this molecular gradient. Therefore, opposing tectal gradients of repellent ephrin-As and of axon growth stimulating EphA3 complement each other to map optic fibers along the rostro-caudal tectal axis.

Background: Cell proliferation plays an important morphogenetic role. This work analyzes the temporalspatial organization of cell proliferation as an attempt to understand its contribution to the chick optic tectum (OT) morphogenesis. Results: A morphogenetic model based on space-dependent differences in cell proliferation is presented. Step1: a medial zone of high mitotic density (mZHMD) appears at the caudal zone. Step2: the mZHMD expands cephalically forming the dorsal curvature and then duplicates into two bilateral ZHMDs (bZHMD). Step3: the bZHMDs move toward the central region of each hemitectum. Step4: the planar expansion of both bZHMD and a relative decrement in the dorsal midline growth produces a dorsal medial groove separating the tectal hemispheres. Step5: a relative caudal displacement of the bZHMDs produces the OT caudal curvature. Numerical sequences derived from records of mitotic cells spatial coordinates, analyzed as stochastic point processes, show that they correspond to 1/f(beta) processes. The spatial organization subsumes deterministic and stochastic components. Conclusions: The deterministic component describes the presence of a long-range influence that installs an asymmetric distribution of cell proliferation, i.e., an asymmetrically located ZHMD that print space-dependent differences onto the tectal corticogenesis. The stochastic component reveals short-range anti-correlations reflecting spatial clusterization and synchronization between neighboring cells. Developmental Dynamics 241:10431061, 2012. (c) 2012 Wiley Periodicals, Inc.

Background Sonic hedgehog (Shh)/Gli pathway plays an important regulatory role on the neuroepithelial cells (NEc) proliferation in the dorsal regions of the developing vertebrate Central Nervous System. The aim of this paper was to analyze the effect of the Shh/Gli signaling pathway activation on the proliferation dynamics and/or the spatial organization of the NEc proliferation activity during early stages of the developing chick optic tectum (OT). In ovo pharmacological gain and loss of hedgehog function approaches were complemented with in vivo electroporation experiments in order to create ectopic sources of either Shh or Gli activator (GliA) proteins in the OT. NEc proliferating activity was analyzed at ED 4/4.5 by recording the spatial co-ordinates of the entire population of mitotic NEc (mNEc) located along OT dorsal-ventral sections. Several space signals (numerical sequences) were derived from the mNEc spatial co-ordinate records and analyzed by different standardized non-linear methods of signal analysis. Results In ovo pharmacologic treatment with cyclopamine resulted in dramatic failure in the OT expansion while the agonist purmorphamine produced the opposite result, a huge expansion of the OT vesicle. Besides, GliA and Shh misexpressions interfere with the formation of the intertectal fissure located along the dorsal midline. This morphogenetic alteration is accompanied by an increase in the mNEc density. There is a gradient in the response of NEcs to Shh and GliA: the increase in mNEc density is maximal near the dorsal regions and decrease towards the OT-tegmental boundary. Biomathematical analyses of the signals derived from the mNEc records show that both Shh and GliA electroporations change the proliferation dynamics and the spatial organization of the mNEc as revealed by the changes in the scaling index estimated by these methods. Conclusions The present results show that the Shh/Gli signaling pathway plays a critical role in the OT expansion and modelling. This effect is probably mediated by a differential mitogenic effect that increases the NEc proliferation and modulates the spatial organization of the NEc proliferation activity.

Neurite growth (neuritogenesis) in vitro is a common methodology in the field of developmental neurobiology. Morphological analyses of growing neurites are usually difficult because their thinness and low contrast usually prevent to observe clearly their shape, number, length and spatial orientation. This paper presents the use of the granulometric size distribution in order to automatically obtain information about the shape, size and spatial orientation of growing axons in tissue cultures. The results here presented show that the granulometric size distribution results in a very useful morphological tool since it allows the automatic detection of growing axons and the precise characterization of a relevant parameter indicative of the axonal growth spatial orientation such as the quantification of the angle of deviation of the growing direction. The developed algorithms automatically quantify this orientation by facilitating the analysis of these images, which is important given the large number of images that need to be processed for this type of study.

Development is often described as temporal sequences of developmental stages (DSs). When tables of DS are defined exclusively in the time domain they cannot discriminate histogenetic differences between different positions along a spatial reference axis. We introduce a table of DSs for the developing chick optic tectum (OT) based on time‐ and space‐dependent changes in quantitative morphometric parameters, qualitative histogenetic features and immunocytochemical pattern of several developmentally active molecules (Notch1, Hes5, NeuroD1, β‐III‐Tubulin, synaptotagmin‐I and neurofilament‐M). Seven DSs and four transitional stages were defined from ED2 to ED12, when the basic OT cortical organization is established, along a spatial developmental gradient axis extending between a zone of maximal and a zone of minimal development. The table of DSs reveals that DSs do not only progress as a function of time but also display a spatially organized propagation along the developmental gradient axis. The complex and dynamic character of the OT development is documented by the fact that several DSs are simultaneously present at any ED or any embryonic stage. The table of DSs allows interpreting how developmental cell behaviors are temporally and spatially organized and explains how different DSs appear as a function of both time and space. The table of DSs provides a reference system to characterize the OT corticogenesis and to reliably compare observations made in different specimens. J. Morphol. 2011. © 2011 Wiley‐Liss, Inc.

It is known that the NMDA-R NR1 subunit is needed for the receptor activity and that under hypoxia the evolution toward apoptosis or neuronal survival depends on the balance NR2A/NR2B subunits. This paper analyzes the effect of acute hypoxia on the above mentioned subunits mRNAs during development. The mean percentage of NR1+ neurons displayed the higher plasticity during development while the NR2A+ neurons the higher stability. Acute hypoxia increased the mean percentage of NR1+ and NR2B+ neurons at ED12 but only that of NR1+ neurons at ED18. Acute hypoxia increased the levels of expression of NR1 and NR2B mRNAs at ED12 without changes in the NR2A mRNA. During early stages there is a higher sensitivity to change the subunits mRNA levels under a hypoxic treatment. At ED12 acute hypoxia increased the probability of co-expression of the NR1–NR2A and NR1–NR2B subunits combinations, the level of NR1 and NR2B and the ratio NR2B/NR2A. These conditions facilitate the evolution towards apoptosis.

How far is neuroepithelial cell proliferation in the developing central nervous system a deterministic process? Or, to put it in a more precise way, how accurately can it be described by a deterministic mathematical model? To provide tracks to answer this question, a deterministic system of transport and diffusion partial differential equations, both physiologically and spatially structured, is introduced as a model to describe the spatially organized process of cell proliferation during the development of the central nervous system. As an initial step towards dealing with the three-dimensional case, a unidimensional version of the model is presented. Numerical analysis and numerical tests are performed. In this work we also achieve a first experimental validation of the proposed model, by using cell proliferation data recorded from histological sections obtained during the development of the optic tectum in the chick embryo.

This investigation analyzes the effect of an acute hypoxic treatment on the level of four (alpha(1), alpha(2), beta(2), and gamma(2)) subunit mRNAs of the GABA(A) receptor in layer "i" of the developing chick optic tectum. Our results show that 1 hr of normobaric acute hypoxia significantly changes the subunit mRNA levels. Different subunit mRNAs display different sensitivity to hypoxia: alpha(1), beta(2), and gamma(2) mRNAs are highly sensitive, whereas alpha(2) mRNA is almost not affected. The sensitivity of the mRNA levels to hypoxia is stage dependent. The mean percentages of variation produced by the hypoxia in the level of expression of the four subunits were 20% at ED12, 5% at ED16, and only 2% at ED18. These changes in the mean percentages of expression modify the probability of coexpression. In the case of double mRNA combinations, the hypoxia produced a mean variation in the probability of coexpression of 37% at ED12, 8% at ED16, and only 4% at ED18. With regard to the triple subunit mRNAs combinations, the variations were 206% at ED12, 11% at ED16, and only 7% at ED18. The quadruple combination values were 1,500% at ED12, 21% at ED16, and only 11% at ED18. This study demonstrates that the subunit mRNA levels are highly sensitive during the early stages, suggesting that GABA(A) receptor composition might undergo environment-dependent plastic changes providing a high degree of plasticity to the GABA neurotransmitter system development.

This investigation analyzes the effect of an acute hypoxic treatment on the level of four (alpha(1), alpha(2), beta(2), and gamma(2)) subunit mRNAs of the GABA(A) receptor in layer "i" of the developing chick optic tectum. Our results show that 1 hr of normobaric acute hypoxia significantly changes the subunit mRNA levels. Different subunit mRNAs display different sensitivity to hypoxia: alpha(1), beta(2), and gamma(2) mRNAs are highly sensitive, whereas alpha(2) mRNA is almost not affected. The sensitivity of the mRNA levels to hypoxia is stage dependent. The mean percentages of variation produced by the hypoxia in the level of expression of the four subunits were 20% at ED12, 5% at ED16, and only 2% at ED18. These changes in the mean percentages of expression modify the probability of coexpression. In the case of double mRNA combinations, the hypoxia produced a mean variation in the probability of coexpression of 37% at ED12, 8% at ED16, and only 4% at ED18. With regard to the triple subunit mRNAs combinations, the variations were 206% at ED12, 11% at ED16, and only 7% at ED18. The quadruple combination values were 1,500% at ED12, 21% at ED16, and only 11% at ED18. This study demonstrates that the subunit mRNA levels are highly sensitive during the early stages, suggesting that GABAA receptor composition might undergo environment-dependent plastic changes providing a high degree of plasticity to the GABA neurotransmitter system development. (c) 2007 Wiley-Liss, Inc.