SUMMARY To provide a temporal framework for the genoarchitecture of brain development, in situ hybridization data were generated for embryonic and postnatal mouse brain at 7 developmental stages for ~2100 genes, processed with an automated informatics pipeline and manually annotated. This resource comprises 434,946 images, 7 reference atlases, an ontogenetic ontology, and tools to explore co-expression of genes across neurodevelopment. Gene sets coinciding with developmental phenomena were identified. A temporal shift in the principles governing the molecular organization of the brain was detected, with transient neuromeric, plate-based organization of the brain present at E11.5 and E13.5. Finally, these data provided a transcription factor code that discriminates brain structures and identifies the developmental age of a tissue, providing a foundation for eventual genetic manipulation or tracking of specific brain structures over development. The resource is available as the Allen Developing Mouse Brain Atlas (developingmouse.brain-map.org).

. In this review, we will describe the principle aspects of CNS development in birds and mammals, starting from early stages of embryogenesis (gastrulation and neurulation) and culminating with the formation of a variety of different regions which contribute to the structural complexity of the brain (regionalization and morphogenesis). We will pay special attention to the cellular and molecular mechanisms involved in neural tube regionalization and the key role played by localized secondary organizers in the patterning of neural primordia. KEY WORDS: patterning, neural plate, neural tube, gastrulation, neurulation, secondary organizer, anterior neural ridge, zona limitans intrathalamica, isthmic organizer Neural plate and neural tube formationA fundamental early step in neural development is the allocation of a group of ectodermal cells as precursors of the entire nervous system (Hemmati-Brivanlou and Melton, 1997). This process involves an inductive interaction first demonstrated in amphibian embryos by Spemann and Mangold in the 1920's (see Spemann and Mangold, 2001). Their experiments which involved the grafting of differently pigmented species of newt established the concept of neural induction as an instructive interaction between the dorsal lip of the blastopore (the "organizer") and the neighboring ectoderm. The discovery of a neural organization center for the amphibian gastrula initiated a search for homologous structures in other vertebrates. Soon thereafter, the equivalent region was discovered in most vertebrate species, including the shield of teleosts. In birds and mammals, the region was named "Hensen's node" and "the node", respectively. When C.H. Waddington transplanted the Hensen node of a chick embryo, he observed the induction of Int. J. Dev. Biol. 54: 7-20 (2010) Abbreviations used in this paper: ANR, anterior neural ridge; AP, anteroposterior; BMP, bone morphogenetic protein; DV, dorso-ventral; FGF, fibroblast growth factor; IsO, Isthmic organizer; ML, medio-lateral; TGF, transforming growth factor; ZLI, zona limitans intrathalamica.an ectopic neural plate or the formation of a partial new embryonic axis containing neural tube, notochord and somites (Waddington, 1933;Waddington, 1936). This demonstration provided the first evidence that in chick embryos, the nervous system is induced by signals from non-neural cells. Recent works demonstrated that the capacity of ectodermal cells to undergo neural differentiation represents their default state. In fact, neural differentiation must be suppressed in the lateral ectoderm by signals transmitted between neighboring cells, in order to develop as epidermis. These molecular signals are members of the bone morphogenetic protein (BMP) subclass of transforming growth factor β (TGF-β)-related proteins (for review see Wittler and Kessel, 2004). C. Vieira et al.Recent studies using chick embryos have shown that neural induction really begins prior to the formation of the organizer region and thus must be initiated by signals derived from other cellul...

Fate-map studies have provided important information in relation to the regional topology of brain areas in different vertebrate species. Moreover, these studies have demonstrated that the distribution of presumptive territories in neural plate and neural tube are highly conserved in vertebrates. The aim of this review is to re-examine and correlate the distribution of presumptive neuroepithelial domains in the chick neural tube with molecular information and discuss recent data. First, we review descriptive fate map studies of neural plate in different vertebrate species that have been studied using diverse fate-mapping methods. Then, we summarize the available data on the localization of neuroepithelial progenitors for the brain subregions in the chick neural tube at stage HH10-11, the most used stage for experimental embryology. This analysis is mainly focused on experimental fate mapping results using quail-chick chimeras.

ABSTRACT

There was an error in the ePress version of Development 138, 4315-4326 published on 24 August 2011.In Fig. 7P, the P-values are not given in the legend. For region 2, P=0.02; for region 3, P=0.003.The final online issue and print copy are correct.We apologise to authors and readers for this error.

A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.

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LIS1 is one of the principal genes related to Type I lissencephaly, a severe human brain malformation characterized by an abnormal neuronal migration in the cortex during embryonic development. This is clinically associated with epilepsy and cerebral palsy in severe cases, as well as a predisposition to developing mental disorders, in cases with a mild phenotype. Although genetic variations in the LIS1 gene have been associated with the development of schizophrenia, little is known about the underlying neurobiological mechanisms. We have studied how the Lis1 gene might cause deficits associated with the pathophysiology of schizophrenia using the Lis1/sLis1 murine model, which involves the deletion of the first coding exon of the Lis1 gene. Homozygous mice are not viable, but heterozygous animals present abnormal neuronal morphology, cortical dysplasia, and enhanced cortical excitability. We have observed reduced number of cells expressing GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) in the hippocampus and the anterior cingulate area, as well as fewer parvalbumin-expressing cells in the anterior cingulate cortex in Lis1/sLis1 mutants compared to control mice. The cFOS protein expression (indicative of neuronal activity) in Lis1/sLis1 mice was higher in the medial prefrontal (mPFC), perirhinal (PERI), entorhinal (ENT), ectorhinal (ECT) cortices, and hippocampus compared to control mice. Our results suggest that deleting the first coding exon of the Lis1 gene might cause cortical anomalies associated with the pathophysiology of schizophrenia.