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Abstract Background The homeobox containing transcription factor Uncx4.1 is, amongst others, expressed in the mouse midbrain. The early expression of this transcription factor in the mouse, as well as in the chick midbrain, points to a conserved function of Uncx4.1, but so far a functional analysis in this brain territory is missing. The goal of the current study was to analyze in which midbrain neuronal subgroups Uncx4.1 is expressed and to examine whether this factor plays a role in the early development of these neuronal subgroups. Results We have shown that Uncx4.1 is expressed in GABAergic, glutamatergic and dopaminergic neurons in the mouse midbrain. In midbrain dopaminergic (mDA) neurons Uncx4.1 expression is particularly high around E11.5 and strongly diminished already at E17.5. The analysis of knockout mice revealed that the loss of Uncx4.1 is accompanied with a 25% decrease in the population of mDA neurons, as marked by tyrosine hydroxylase (TH), dopamine transporter (DAT), Pitx3 and Ngn2. In contrast, the number of glutamatergic Pax6-positive cells was augmented, while the GABAergic neuron population appears not affected in Uncx4.1-deficient embryos. Conclusion We conclude that Uncx4.1 is implicated in the development of mDA neurons where it displays a unique temporal expression profile in the early postmitotic stage. Our data indicate that the mechanism underlying the role of Uncx4.1 in mDA development is likely related to differentiation processes in postmitotic stages, and where Ngn2 is engaged. Moreover, Uncx4.1 might play an important role during glutamatergic neuronal differentiation in the mouse midbrain.

Colour agnosia is a disorder that impairs colour knowledge (naming, recognition) despite intact colour perception. Previously, we have identified the first and only-known family with hereditary developmental colour agnosia. The aim of the current study was to explore genomic regions and candidate genes that potentially cause this trait in this family. For three family members with developmental colour agnosia and three unaffected family members CGH-array analysis and exome sequencing was performed, and linkage analysis was carried out using DominantMapper, resulting in the identification of 19 cosegregating chromosomal regions. Whole exome sequencing resulted in 11 rare coding variants present in all affected family members with developmental colour agnosia and absent in unaffected members. These variants affected genes that have been implicated in neural processes and functions (CACNA2D4, DDX25, GRINA, MYO15A) or that have an indirect link to brain function, development or disease (MAML2, STAU1, TMED3, RABEPK), and a remaining group lacking brain expression or involved in non-neural traits (DEPDC7, OR1J1, OR8D4). Although this is an explorative study, the small set of candidate genes that could serve as a starting point for unravelling mechanisms of higher level cognitive functions and cortical specialization, and disorders therein such as developmental colour agnosia. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tins.2008.11.002 Byline: J. Peter H. Burbach, Bert van der Zwaag Abstract: Although autism and schizophrenia are considered to be distinct neuropsychiatric developmental disorders, recent studies indicate that they share genetic factors. The same chromosomal rearrangements and several single genes have emerged as genetic risks in both disorders. One such gene is contactin-associated protein-2 (CNTNAP2). These findings raise the possibility that these neuropsychiatric disorders share pathogenic mechanisms and that similar defects in biological pathways of brain development might underlie the phenotypic spectrum of these disorders. Author Affiliation: Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, P.O. Box 85060, 3508 AB Utrecht, The Netherlands

Byline: Sofia Lopes da Silva, J. Peter H. Burbach Abstract: Nuclear hormone receptors comprise a superfamily of over 40 transcription factors. About half of them are classical receptors for lipophilic ligands such as steroids and vitamins. Almost all of these true receptors are present in the brain, where they transduce chemical signals from endocrine organs or signals of nutritional origin into cellular responses. The other members resemble the classical receptors in structure, but have no known ligands, and are hence called 'orphan receptors'. The issue of whether ligands for nuclear orphan receptors exist is controversial. Evidence is emerging that orphan receptors might be activated by signal transduction pathways or might be constitutive enhancers or repressors that interact with the classical receptors. Thus, nuclear orphan receptors are placed in strategic positions in the regulation of gene expression in the nervous system. Author Affiliation: Rudolf Magnus Institute for Neurosciences, Dept of Medical Pharmacology, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tins.2006.09.003 Byline: J. Peter H. Burbach, Marten P. Smidt Abstract: In a screen for homeobox transcription factors expressed in the embryonic ventral midbrain, Andersson et al. recently identified Lmx1a and Msx1. Using in ovo electroporation in chick embryos, they showed that these factors are crucial for initiating the differentiation of neuroepithelial progenitor neurons into mesodiencephalic dopaminergic (mdDA) neurons. Lmx1a also initiated a developmental program that drove an mdDA phenotype in mouse embryonic stem cells. This indicates that these factors can be exploited in cell-replacement strategies for treatment of Parkinson's disease. Author Affiliation: Rudolf Magnus Institute of Neuroscience, Department of Pharmacology and Anatomy, University Medical Center Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands

Autism spectrum disorder (ASD) is characterized by impaired social interaction, language delay and repetitive or restrictive behaviors. With increasing prevalence, ASD is currently estimated to affect 0.5–2.0% of the global population. However, its etiology remains unclear due to high genetic and phenotypic heterogeneity. Copy number variations (CNVs) are implicated in several forms of syndromic ASD and have been demonstrated to contribute toward ASD development by altering gene dosage and expression. Increasing evidence points toward the p-arm of chromosome 3 (chromosome 3p) as an ASD risk locus. Deletions occurring at chromosome 3p result in 3p-deletion syndrome (Del3p), a rare genetic disorder characterized by developmental delay, intellectual disability, facial dysmorphisms and often, ASD or ASD-associated behaviors. Therefore, we hypothesize that overlapping molecular mechanisms underlie the pathogenesis of Del3p and ASD. To investigate which genes encoded in chromosome 3p could contribute toward Del3p and ASD, we performed a comprehensive literature review and collated reports investigating the phenotypes of individuals with chromosome 3p CNVs. We observe that high frequencies of CNVs occur in the 3p26.3 region, the terminal cytoband of chromosome 3p. This suggests that CNVs disrupting genes encoded within the 3p26.3 region are likely to contribute toward the neurodevelopmental phenotypes observed in individuals affected by Del3p. The 3p26.3 region contains three consecutive genes encoding closely related neuronal immunoglobulin cell adhesion molecules (IgCAMs): Close Homolog of L1 (CHL1), Contactin-6 (CNTN6), and Contactin-4 (CNTN4). CNVs disrupting these neuronal IgCAMs may contribute toward ASD phenotypes as they have been associated with key roles in neurodevelopment. CHL1, CNTN6, and CNTN4 have been observed to promote neurogenesis and neuronal survival, and regulate neuritogenesis and synaptic function. Furthermore, there is evidence that these neuronal IgCAMs possess overlapping interactomes and participate in common signaling pathways regulating axon guidance. Notably, mouse models deficient for these neuronal IgCAMs do not display strong deficits in axonal migration or behavioral phenotypes, which is in contrast to the pronounced defects in neuritogenesis and axon guidance observed in vitro. This suggests that when CHL1, CNTN6, or CNTN4 function is disrupted by CNVs, other neuronal IgCAMs may suppress behavioral phenotypes by compensating for the loss of function. [ABSTRACT FROM AUTHOR]

Latrophilins (LPHNs) are adhesion GPCRs that are originally discovered as spider's toxin receptors, but are now known to be involved in brain development and linked to several neuronal and non-neuronal disorders. Latrophilins act in conjunction with other cell adhesion molecules and may play a leading role in its network organization. Here, we focus on the main protein partners of latrophilins, namely teneurins, FLRTs and contactins and summarize their respective temporal and spatial expression patterns, links to neurodevelopmental disorders as well as their structural characteristics. We discuss how more recent insights into the separate cell biological functions of these proteins shed light on the central role of latrophilins in this network. We postulate that latrophilins control the refinement of synaptic properties of specific subtypes of neurons, requiring discrete combinations of proteins. [ABSTRACT FROM AUTHOR]

Astrocytes contribute to the formation, function, and plasticity of synapses. Their processes enwrap the neuronal components of the tripartite synapse, and due to this close interaction they are perfectly positioned to modulate neuronal communication. The interaction between astrocytes and synapses is facilitated by cell adhesion molecules and matricellular proteins, which have been implicated in the formation and functioning of tripartite synapses. The importance of such neuron-astrocyte integration at the synapse is underscored by the emerging role of astrocyte dysfunction in synaptic pathologies such as autism and schizophrenia. Here we review astrocyte-expressed cell adhesion molecules and matricellular molecules that play a role in integration of neurons and astrocytes within the tripartite synapse. [ABSTRACT FROM AUTHOR]

The development of mesodiencephalic dopaminergic (mdDA) neurons located in the substantia nigra compacta (SNc) and ventral tegmental area (VTA) follow a number of stages marked by distinct events. After preparation of the region by signals that provide induction and patterning, several transcription factors have been identified, which are involved in specifying the neuronal fate of these cells. The specific vulnerability of SNc neurons is thought to root in these specific developmental programs. The present study examines the positions of young postmitotic mdDA neurons to relate developmental position to mdDA subset specific markers. MdDA neurons were mapped relative to the neuromeric domains (prosomeres 1-3 (P1-3), midbrain, and hindbrain) as well as the longitudinal subdivisions (floor plate, basal plate, alar plate), as proposed by the prosomeric model. We found that postmitotic mdDA neurons are located mainly in the floorplate domain and very few in slightly more lateral domains. Moreover, mdDA neurons are present along a large proportion of the anterior/posterior axis extending from the midbrain to P3 in the diencephalon. The specific positions relate to some extent to the presence of specific subset markers as Ahd2. In the adult stage more of such subsets specific expressed genes are present and may represent a molecular map defining molecularly distinct groups of mdDA neurons. [ABSTRACT FROM AUTHOR]

Development of meso-diencephalic dopamine (mdDA) neurons requires the combined actions of the orphan nuclear receptor Nurr1 and the paired-like homeobox transcription factor Pitx3. Whereas all mdDA neurons require Nurr1 for expression of Th and survival, dependence on Pitx3 is displayed only by the mdDA subpopulation that will form the substantia nigra (SNc). Previously, we have demonstrated that Pitx3-/- embryos lack the expression of the retinoic acid (RA)-generating enzyme Ahd2, which is normally selectively expressed in the Pitx3- dependent DA neurons of the SNc. Restoring RA signaling in Pitx3-/- embryos revealed a selective dependence of SNc neurons on the presence of RA for differentiation into Th-positive neurons and maintenance throughout embryonic development. Whereas these data are suggestive of an important developmental role for RA in neurons of the SNc, it remained unclear whether other Nurr1 and Pitx3 target genes depend on RA signaling in a manner similar to Th. In the search for genes that were affected in Pitx3-deficient mdDA neurons and restored upon embryonic RA treatment, we provide evidence that Delta-like 1, D2R (Drd2) and Th are regulated by Pitx3 and RA signaling, which influences the mdDA terminal differentiated phenotype. Furthermore, we show that regulation of Ahd2-mediated RA signaling represents only one aspect of the Pitx3 downstream cascade, as Vmat2, Dat, Ahd2 (Aldh1a1), En1, En2 and Cck were unaffected by RA treatment and are (subset) specifically modulated by Pitx3. In conclusion, our data reveal several RA-dependent and -independent aspects of the Pitx3-regulated gene cascade, suggesting that Pitx3 acts on multiple levels in the molecular subset-specification of mdDA neurons. [ABSTRACT FROM AUTHOR]

Dopaminergic neurons in the mesodiencephalon(mdDA neurons)make precise synaptic connections with targets in the forebrain via the mesostriatal, mesolimbic, and mesoprefrontal pathways. Because of the functional importance of these remarkably complex ascending axon pathways and their implication in human disease, the mechanisms underlying the development of these connections are of considerable interest. Despite extensive in vitro studies, the molecular determinants that ensure the perfect formation of these pathways in vivo remain mostly unknown. Here, we determine the embryonic origin and ontogeny of the mouse mesoprefrontal pathway and use these data to reveal an unexpected requirement for semaphorin 3F (Sema3F) and its receptor neuropilin-2 (Npn-2) during mdDA pathway development using tissue culture approaches and analysis of sema3F-/-, npn-2-/-, and npn-2-/-;TH-Cre mice. We show that Sema3F is a bifunctional guidance cue for mdDA axons, some of which have the remarkable ability to regulate their responsiveness to Sema3F as they develop. During early developmental stages, Sema3F chemorepulsion controls previously uncharacterized aspects of mdDA pathway development through both Npn-2-dependent (axon fasciculation and channeling) and Npn-2-independent (rostral growth) mechanisms. Later on, chemoattraction mediated by Sema3F and Npn-2 is required to orient mdDA axon projections in the cortical plate of the medial prefrontal cortex. This latter finding demonstrates that regulation of axon orientation in the target field occurs by chemoattractive mechanisms, and this is likely to also apply to other neural systems. In all, this study provides a framework for additional dissection of the molecular basis of mdDA pathway development and disease. [ABSTRACT FROM AUTHOR]

Dopaminergic neurons located in the ventral mesodiencephalon are essential for the control of voluntary movement and the regulation of emotion, and are severely affected in neurodegenerative diseases such as Parkinson's disease. Recent advances in molecular biology and mouse genetics have helped to unravel the mechanisms involved in the development of mesodiencephalic dopaminergic (mdDA) neurons, including their specification, migration and differentiation, as well as the processes that govern axonal pathfinding and their specific patterns of connectivity and maintenance. Here, we follow the developmental path of these neurons with the goal of generating a molecular code that could be exploited in cell-replacement strategies to treat diseases such as Parkinson's disease. [ABSTRACT FROM AUTHOR]