Rapid ovarian transcript changes during the onset of premature ovarian insufficiency.

The manuscript has been submitted without altering abstract in line with Reproduction's Flexible Submission Process. The abstract is extended and thus does not fit this space.

The Enigmatic Reissner's Fiber and the Origin of Chordates.

Reissner's fiber (RF) is a secreted filament that floats in the neural canal of chordates. Since its discovery in 1860, there has been no agreement on its primary function, and its strong conservation across chordate species has remained a mystery for comparative neuroanatomists. Several findings, including the chemical composition and the phylogenetic history of RF, clinical observations associating RF with the development of the neural canal, and more recent studies suggesting that RF is needed to develop a straight vertebral column, may shed light on the functions of this structure across chordates. In this article, we will briefly review the evidence mentioned above to suggest a role of RF in the origin of fundamental innovations of the chordate body plan, especially the elongation of the neural tube and maintenance of the body axis. We will also mention the relevance of RF for medical conditions like hydrocephalus, scoliosis of the vertebral spine and possibly regeneration of the spinal cord.

Morphological evolution of the vertebrate forebrain: From mechanical to cellular processes.

Although the cerebral hemispheres are among the defining characters of vertebrates, each vertebrate class is characterized by a different anatomical organization of this structure, which has become highly problematic for comparative neurobiology. In this article, we discuss some mechanisms involved in the generation of this morphological divergence, based on simple spatial constraints for neurogenesis and mechanical forces generated by increasing neuronal numbers during development, and the different cellular strategies used by each group to overcome these limitations. We expect this view to contribute to unify the diverging vertebrate brain morphologies into general, simple mechanisms that help to establish homologies across groups.

From sauropsids to mammals and back: New approaches to comparative cortical development.

Evolution of the mammalian neocortex (isocortex) has been a persisting problem in neurobiology. While recent studies have attempted to understand the evolutionary expansion of the human neocortex from rodents, similar approaches have been used to study the changes between reptiles, birds, and mammals. We review here findings from the past decades on the development, organization, and gene expression patterns in various extant species. This review aims to compare cortical cell numbers and neuronal cell types to the elaboration of progenitor populations and their proliferation in these species. Several progenitors, such as the ventricular radial glia, the subventricular intermediate progenitors, and the subventricular (outer) radial glia, have been identified but the contribution of each to cortical layers and cell types through specific lineages, their possible roles in determining brain size or cortical folding, are not yet understood. Across species, larger, more diverse progenitors relate to cortical size and cell diversity. The challenge is to relate the radial and tangential expansion of the neocortex to the changes in the proliferative compartments during mammalian evolution and with the changes in gene expression and lineages evident in various sectors of the developing brain. We also review the use of recent lineage tracing and transcriptomic approaches to revisit theories and to provide novel understanding of molecular processes involved in specification of cortical regions.

Olfaction, navigation, and the origin of isocortex.

There are remarkable similarities between the brains of mammals and birds in terms of microcircuit architecture, despite obvious differences in gross morphology and development. While in reptiles and birds the most expanding component (the dorsal ventricular ridge) displays an overall nuclear shape and derives from the lateral and ventral pallium, in mammals a dorsal pallial, six-layered isocortex shows the most remarkable elaboration. Regardless of discussions about possible homologies between mammalian and avian brains, a main question remains in explaining the emergence of the mammalian isocortex, because it represents a unique phenotype across amniotes. In this article, we propose that the origin of the isocortex was driven by behavioral adaptations involving olfactory driven goal-directed and navigating behaviors. These adaptations were linked with increasing sensory development, which provided selective pressure for the expansion of the dorsal pallium. The latter appeared as an interface in olfactory-hippocampal networks, contributing somatosensory information for navigating behavior. Sensory input from other modalities like vision and audition were subsequently recruited into this expanding region, contributing to multimodal associative networks.

Pallial patterning and the origin of the isocortex.

Together with a complex variety of behavioral, physiological, morphological, and neurobiological innovations, mammals are characterized by the development of an extensive isocortex (also called neocortex) that is both laminated and radially organized, as opposed to the brain of birds and reptiles. In this article, we will advance a developmental hypothesis in which the mechanisms of evolutionary brain growth remain partly conserved across amniotes (mammals, reptiles and birds), all based on Pax6 signaling or related morphogens. Despite this conservatism, only in mammals there is an additional upregulation of dorsal and anterior signaling centers (the cortical hem and the anterior forebrain, respectively) that promoted a laminar and a columnar structure into the neocortex. It is possible that independently, some birds also developed an upregulated dorsal pallium.

Prenatal stress down-regulates Reelin expression by methylation of its promoter and induces adult behavioral impairments in rats.

Prenatal stress causes predisposition to cognitive and emotional disturbances and is a risk factor towards the development of neuropsychiatric conditions like depression, bipolar disorders and schizophrenia. The extracellular protein Reelin, expressed by Cajal-Retzius cells during cortical development, plays critical roles on cortical lamination and synaptic maturation, and its deregulation has been associated with maladaptive conditions. In the present study, we address the effect of prenatal restraint stress (PNS) upon Reelin expression and signaling in pregnant rats during the last 10 days of pregnancy. Animals from one group, including control and PNS exposed fetuses, were sacrificed and analyzed using immunohistochemical, biochemical, cell biology and molecular biology approaches. We scored changes in the expression of Reelin, its signaling pathway and in the methylation of its promoter. A second group included control and PNS exposed animals maintained until young adulthood for behavioral studies. Using the optical dissector, we show decreased numbers of Reelin-positive neurons in cortical layer I of PNS exposed animals. In addition, neurons from PNS exposed animals display decreased Reelin expression that is paralleled by changes in components of the Reelin-signaling cascade, both in vivo and in vitro. Furthermore, PNS induced changes in the DNA methylation levels of the Reelin promoter in culture and in histological samples. PNS adult rats display excessive spontaneous locomotor activity, high anxiety levels and problems of learning and memory consolidation. No significant visuo-spatial memory impairment was detected on the Morris water maze. These results highlight the effects of prenatal stress on the Cajal-Retzius neuronal population, and the persistence of behavioral consequences using this treatment in adults, thereby supporting a relevant role of PNS in the genesis of neuropsychiatric diseases. We also propose an in vitro model that can yield new insights on the molecular mechanisms behind the effects of prenatal stress.

The long non-coding RNA Dali is an epigenetic regulator of neural differentiation.

Many intergenic long noncoding RNA (lncRNA) loci regulate the expression of adjacent protein coding genes. Less clear is whether intergenic lncRNAs commonly regulate transcription by modulating chromatin at genomically distant loci. Here, we report both genomically local and distal RNA-dependent roles of Dali, a conserved central nervous system expressed intergenic lncRNA. Dali is transcribed downstream of the Pou3f3 transcription factor gene and its depletion disrupts the differentiation of neuroblastoma cells. Locally, Dali transcript regulates transcription of the Pou3f3 locus. Distally, it preferentially targets active promoters and regulates expression of neural differentiation genes, in part through physical association with the POU3F3 protein. Dali interacts with the DNMT1 DNA methyltransferase in mouse and human and regulates DNA methylation status of CpG island-associated promoters in trans. These results demonstrate, for the first time, that a single intergenic lncRNA controls the activity and methylation of genomically distal regulatory elements to modulate large-scale transcriptional programmes.

Adult pallium transcriptomes surprise in not reflecting predicted homologies across diverse chicken and mouse pallial sectors.

The thorniest problem in comparative neurobiology is the identification of the particular brain region of birds and reptiles that corresponds to the mammalian neocortex [Butler AB, Reiner A, Karten HJ (2011) Ann N Y Acad Sci 1225:14-27; Wang Y, Brzozowska-Prechtl A, Karten HJ (2010) Proc Natl Acad Sci USA 107(28):12676-12681]. We explored which genes are actively transcribed in the regions of controversial ancestry in a representative bird (chicken) and mammal (mouse) at adult stages. We conducted four analyses comparing the expression patterns of their 5,130 most highly expressed one-to-one orthologous genes that considered global patterns of expression specificity, strong gene markers, and coexpression networks. Our study demonstrates transcriptomic divergence, plausible convergence, and, in two exceptional cases, conservation between specialized avian and mammalian telencephalic regions. This large-scale study potentially resolves the complex relationship between developmental homology and functional characteristics on the molecular level and settles long-standing evolutionary debates.

Maternal-fetal unit interactions and eutherian neocortical development and evolution.

The conserved brain design that primates inherited from early mammals differs from the variable adult brain size and species-specific brain dominances observed across mammals. This variability relies on the emergence of specialized cerebral cortical regions and sub-compartments, triggering an increase in brain size, areal interconnectivity and histological complexity that ultimately lies on the activation of developmental programs. Structural placental features are not well correlated with brain enlargement; however, several endocrine pathways could be tuned with the activation of neuronal progenitors in the proliferative neocortical compartments. In this article, we reviewed some mechanisms of eutherians maternal-fetal unit interactions associated with brain development and evolution. We propose a hypothesis of brain evolution where proliferative compartments in primates become activated by "non-classical" endocrine placental signals participating in different steps of corticogenesis. Changes in the inner placental structure, along with placenta endocrine stimuli over the cortical proliferative activity would allow mammalian brain enlargement with a concomitant shorter gestation span, as an evolutionary strategy to escape from parent-offspring conflict.

The impact of gene expression analysis on evolving views of avian brain organization.

Recent studies have presented data on adult and developing avian brain organization. Jarvis et al. ([2013] J Comp Neurol. 521:3614-3665) identify four pallial and two subpallial gene expression domains and demonstrate that the mesopallium and adjoining divisions of the hyperpallium (hyperpallium intercalatum and hyperpallium densocellulare), have very similar gene expression profiles to each other, distinct from those of the nidopallium, the arcopallium, and the more distant divisions of the hyperpallium (hyperpallium apicale). The study proposes an update of the current nomenclature (Jarvis et al. [2005] Nat Rev Neurosci. 6:151-159). The authors perform densitometric quantifications of the in situ expression of 50 selected genes, use correlations of distances between vectors that represent these gene expression patterns within the 23 avian brain regions of their study, and group them according to similarity in their expression profiles. The generated cluster tree further supports their argument for a new terminology. The authors hypothesize that the mesopallium and adjoining divisions of the hyperpallium have a common developmental origin, and in the accompanying paper (Chen et al. [2013] J Comp Neurol. 521:3666-3701) show that these structures/subdivisions initially form continuous gene expression domains. With subsequent development these domains fold into distinct subdivisions in the dorsal and ventral avian pallium, forming mirror images to each other. Jarvis et al. ([2013] J Comp Neurol. 521:3614-3665) also demonstrate interesting principles of the functional organization of the avian brain by showing that specific sensory stimulation or motor behavior elicits gene expression in functional units perpendicular to the axis of the gene expression reversal and compare their arrangements and cell types with mammalian cortical columns.

Origen y Migración de Células Troncales / Stem Cells Origin and Migration

La generación de progenitores celulares, su migración y distribución a través del organismo, es determinante en la generación de divergencia morfológica y evolución de las distintas especies de vertebrados. Las células progenitoras transitan por diferentes compartimentos durante el desarrollo embrionario y su exposición a diferentes medioambientes tisulares estimula la activación de programas específicos de diferenciación. En este capítulo discutiremos el origen de diferentes poblaciones de células migratorias, tales como las células madre embrionarias, las células germinales primordiales y las células de la cresta neural, con un enfoque en los distintos factores moleculares activados durante la migración hacia distintos compartimientos embrionarios.

Generation, migration and distribution of stem cells throughout the body are a major process in the generation of morphological divergence and evolution in different species of vertebrates. Progenitor cells pass through different compartments during embryonic development and the exposition to different tissue environments stimulates the activation of specific differentiation programs. In this chapter we discuss the origin of different migratory cell populations, such as embryonic stem cells, primordial germ cells and neural crest cells, with focus on the different molecular factors activated during migration to different embryonic compartments.

From tetrapods to primates: conserved developmental mechanisms in diverging ecological adaptations.

Primates are endowed with a brain about twice the size that of a mammal with the same body size, and humans have the largest brain relative to body size of all animals. This increase in brain size may be related to the acquisition of higher cognitive skills that permitted more complex social interactions, the evolution of culture, and the eventual ability to manipulate the environment. Nevertheless, in its internal structure, the primate brain shares a very conserved design with other mammals, being covered by a six-layered neocortex that, although expands disproportionately to other brain components, it does so following relatively well-defined allometric trends. Thus, the most fundamental events generating the basic design of the primate and human brain took place before the appearance of the first primate-like animal. Presumably, the earliest mammals already displayed a brain morphology radically different from that of their ancestors and that of their sister group, the reptiles, being characterized by the presence of an incipient neocortex that underwent an explosive growth in subsequent mammal evolution. In this chapter, we propose an integrative hypothesis for the origin of the mammalian neocortex, by considering the developmental modifications, functional networks, and ecological adaptations involved in the generation of this structure during the cretaceous period. Subsequently, the expansion of the primate brain is proposed to have relied on the amplification of the same, or very similar, developmental mechanisms as those involved in its primary origins, even in different ecological settings.

Hypothesis on the dual origin of the Mammalian subplate.

The development of the mammalian neocortex relies heavily on subplate. The proportion of this cell population varies considerably in different mammalian species. Subplate is almost undetectable in marsupials, forms a thin, but distinct layer in mouse and rat, a larger layer in carnivores and big-brained mammals as pig, and a highly developed embryonic structure in human and non-human primates. The evolutionary origin of subplate neurons is the subject of current debate. Some hypothesize that subplate represents the ancestral cortex of sauropsids, while others consider it to be an increasingly complex phylogenetic novelty of the mammalian neocortex. Here we review recent work on expression of several genes that were originally identified in rodent as highly and differentially expressed in subplate. We relate these observations to cellular morphology, birthdating, and hodology in the dorsal cortex/dorsal pallium of several amniote species. Based on this reviewed evidence we argue for a third hypothesis according to which subplate contains both ancestral and newly derived cell populations. We propose that the mammalian subplate originally derived from a phylogenetically ancient structure in the dorsal pallium of stem amniotes, but subsequently expanded with additional cell populations in the synapsid lineage to support an increasingly complex cortical plate development. Further understanding of the detailed molecular taxonomy, somatodendritic morphology, and connectivity of subplate in a comparative context should contribute to the identification of the ancestral and newly evolved populations of subplate neurons.

Comparative aspects of subplate zone studied with gene expression in sauropsids and mammals.

There is currently a debate about the evolutionary origin of the earliest generated cortical preplate neurons and their derivatives (subplate and marginal zone). We examined the subplate with murine markers including nuclear receptor related 1 (Nurr1), monooxygenase Dbh-like 1 (Moxd1), transmembrane protein 163 (Tmem163), and connective tissue growth factor (Ctgf) in developing and adult turtle, chick, opossum, mouse, and rat. Whereas some of these are expressed in dorsal pallium in all species studied (Nurr1, Ctgf, and Tmem163), we observed that the closely related mouse and rat differed in the expression patterns of several others (Dopa decarboxylase, Moxd1, and thyrotropin-releasing hormone). The expression of Ctgf, Moxd1, and Nurr1 in the oppossum suggests a more dispersed subplate population in this marsupial compared with mice and rats. In embryonic and adult chick brains, our selected subplate markers are primarily expressed in the hyperpallium and in the turtle in the main cell dense layer of the dorsal cortex. These observations suggest that some neurons that express these selected markers were present in the common ancestor of sauropsids and mammals.

AChE-rich magnopyramidal neurons have a left-right size asymmetry in Broca's area.

Acetylcholinesterase-rich neurons (AChERN) are a particular group of pyramidal neurons, displaying a specific laminar and ontogenetic pattern in the cerebral cortex of human and nonhuman primates. Using histochemistry and morphometrical methods, we have found a layer 3 magnopyramidal AChERN left-right size asymmetry restricted to Brodmann's area 45, a component of Broca's language area. This structural feature could be related to functional lateralization associated to syntactic processing and phonological working memory, and is consistent with a non-cholinergic role of AChE possibly linked to neuroplastic processes in the human neocortex.