FGF15 promotes neurogenesis and opposes FGF8 function during neocortical development

<p>Abstract</p> <p>Background</p> <p>Growth, differentiation and regional specification of telencephalic domains, such as the cerebral cortex, are regulated by the interplay of secreted proteins produced by patterning centers and signal transduction systems deployed in the surrounding neuroepithelium. Among other signaling molecules, members of the fibroblast growth factor (FGF) family have a prominent role in regulating growth, differentiation and regional specification. In the mouse telencephalon the rostral patterning center expresses members of the <it>Fgf </it>family (<it>Fgf8</it>, <it>Fgf15</it>, <it>Fgf17</it>, <it>Fgf18</it>). FGF8 and FGF17 signaling have major roles in specification and morphogenesis of the rostroventral telencephalon, whereas the functions of FGF15 and FGF18 in the rostral patterning center have not been established.</p> <p>Results</p> <p>Using <it>Fgf15</it>^-/-mutant mice, we provide evidence that FGF15 suppresses proliferation, and that it promotes differentiation, expression of <it>CoupTF1 </it>and caudoventral fate; thus, reducing <it>Fgf15 </it>and <it>Fgf8 </it>dosage have opposite effects. Furthermore, we show that FGF15 and FGF8 differentially phosphorylate ERK (p42/44), AKT and S6 in cultures of embryonic cortex. Finally, we show that FGF15 inhibits proliferation in cortical cultures.</p> <p>Conclusion</p> <p>FGF15 and FGF8 have distinct signaling properties, and opposite effects on neocortical patterning and differentiation; FGF15 promotes <it>CoupTF1 </it>expression, represses proliferation and promotes neural differentiation.</p

Enhancing Mitosis Quantification and Detection in Meningiomas With Computational Digital Pathology

Mitosis is a critical criterion for meningioma grading. However, pathologists\u27 assessment of mitoses is subject to significant inter-observer variation due to challenges in locating mitosis hotspots and accurately detecting mitotic figures. To address this issue, we leverage digital pathology and propose a computational strategy to enhance pathologists\u27 mitosis assessment. The strategy has two components: (1) A depth-first search algorithm that quantifies the mathematically maximum mitotic count in 10 consecutive high-power fields, which can enhance the preciseness, especially in cases with borderline mitotic count. (2) Implementing a collaborative sphere to group a set of pathologists to detect mitoses under each high-power field, which can mitigate subjective random errors in mitosis detection originating from individual detection errors. By depth-first search algorithm (1) , we analyzed 19 meningioma slides and discovered that the proposed algorithm upgraded two borderline cases verified at consensus conferences. This improvement is attributed to the algorithm\u27s ability to quantify the mitotic count more comprehensively compared to other conventional methods of counting mitoses. In implementing a collaborative sphere (2) , we evaluated the correctness of mitosis detection from grouped pathologists and/or pathology residents, where each member of the group annotated a set of 48 high-power field images for mitotic figures independently. We report that groups with sizes of three can achieve an average precision of 0.897 and sensitivity of 0.699 in mitosis detection, which is higher than an average pathologist in this study (precision: 0.750, sensitivity: 0.667). The proposed computational strategy can be integrated with artificial intelligence workflow, which envisions the future of achieving a rapid and robust mitosis assessment by interactive assisting algorithms that can ultimately benefit patient management

Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures

: Astrocytes are critical for the development and function of synapses. There are notable species differences between human astrocytes and commonly used animal models. Yet, it is unclear whether astrocytic genes involved in synaptic function are stable or exhibit dynamic changes associated with disease states and age in humans, which is a barrier in understanding human astrocyte biology and its potential involvement in neurological diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. We found that human astrocytes in tumor-surrounding regions downregulate genes involved in synaptic function and sensing of signals in the microenvironment, suggesting involvement of peri-tumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of cytokine signaling, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified subtle sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurological disorders. Overall, genes involved in synaptic function exhibit dynamic changes in the peritumor microenvironment and aging. This data provides powerful new insights into human astrocyte biology in several biologically relevant states, that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans.SIGNIFICANCE STATEMENTAstrocytes are an abundant class of cells playing integral roles at synapses. Astrocyte dysfunction is implicated in a variety of human neurological diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found that peritumor and aging astrocytes downregulate genes involved in astrocyte-synapse interactions. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease

Human von Economo Neurons Express Transcription Factors Associated with Layer V Subcerebral Projection Neurons

The von Economo neurons (VENs) are large bipolar Layer V projection neurons found chiefly in the anterior cingulate and frontoinsular cortices. Although VENs have been linked to prevalent illnesses such as frontotemporal dementia, autism, and schizophrenia, little is known about VEN identity, including their major projection targets. Here, we undertook a developmental transcription factor expression study, focusing on markers associated with specific classes of Layer V projection neurons. Using mRNA in situ hybridization, we found that VENs prominently express FEZF2 and CTIP2, transcription factors that regulate the fate and differentiation of subcerebral projection neurons, in humans aged 3 months to 65 years. In contrast, few VENs expressed markers associated with callosal or corticothalamic projections. These findings suggest that VENs may represent a specialized Layer V projection neuron for linking cortical autonomic control sites to brainstem or spinal cord regions

The avian telencephalic subpallium originates inhibitory neurons that invade tangentially the pallium (Dorsal Ventricular Ridge and Cortical Areas)

Recent data on the development of the mammalian neocortex support that the majority of its inhibitory GABAergic interneurons originate within the subpallium (ganglionic eminences). Support for such tangential migration into the pallium has come from experiments using fluorescent tracers or lineage analysis with retrovirus, and the phenotypes of mutant mice with different abnormalities in the developing subpallium. In the present study, we describe tangential migration of subpallial-derived neurons in the developing chick telencephalon. Using quail–chick grafts, we precisely identified the neuroepithelial origin, time-course, and pathways of migration, as well as the identity and relative distribution of the diverse tangentially migrated neurons. The analysis of selective grafts of the pallidal and striatal primordia allowed us to determine the relative contribution of each primordium to the population of migrating neurons. Moreover, we found that, like in mammals, the vast majority of the GABAergic and calbindin-immunoreactive neurons within the pallium (dorsal ventricular ridge and cortical areas) have an extracortical, subpallial origin. Our results suggest that the telencephalon of birds and mammals share developmental mechanisms for the origin and migration of their cortical interneurons, which probably first evolved at an earlier stage in the radiation of vertebrates than was thought before.I.C. received a FPI Fellowship from Fundacion Seneca (Murcia). This work was supported by Fundacion Seneca (Murcia) 708/CV/99, European Community contracts BIO4-98-0309, QLG2-99-00793, QLG3-2000-01556, and QLG3-2000-01625 (to S.M.); Fundacion Seneca (Murcia) PB14/FS/97, CICYT PB98-0397, and EEC contract BIO4-CT96-042 (to L.P.).Peer reviewe

Calretinin in pretecto- and olivocerebellar projections in the chick: Immunohistochemical and experimental study

Calretinin (CaR) is a calcium-binding protein that is distributed extensively in the central nervous system. It is localized in the cell bodies and neurites of specific neuronal populations and serves, therefore, as a reliable anatomical marker. Some components of the pretectocerebellar projection, which connects specific pretectal nuclei to caudal cerebellar folia, are concerned with the cerebellar control of visual reflexes. We investigated the distribution of pretectocerebellar-projecting neurons in relation to cells that show CaR immunoreactivity. Cells that project to the cerebellar cortex in the diencephalic primary visual nuclei and in other grisea, like the nucleus spiriformis medialis and the nucleus dorsofrontalis, colocalized with those that appeared to be immunolabeled intensely with anti-CaR antiserum. To explore the hypothesis of a common developmental origin of these pretectal cerebellopetal neurons, we also investigated the development of CaR-immunopositive cells in the chick pretectum and the arrival of their fibers in the cerebellum, from 10 days of incubation (stage 36) to posthatching stages. Finally, we analyzed the source of CaR+ climbing fibers and found a subpopulation of CaR+ cells in the inferior olivary nucleus. On the whole, these results suggest that there is a common developmental origin of pretectal cerebellopetal neurons, some of which share the property of CaR expression. The functional significance of this correlation needs to be investigated.Grant sponsor: Spanish DGICYT; Grant number: PB93–1137; Grantsponsor: Human Frontiers; Grant number: 41/95B; Grant sponsor: EC;Grant numbers: BMH1-CT94–1378, BIO2-CT93–0012, and BMH4-CT96–0249.Peer reviewe

Fate map of the avian anterior forebrain at the four-somite stage, based on the analysis of quail-chick chimeras

To better understand the topological organization of the primordia within the anterior forebrain, we made a fate map of the rostral neural plate in the chick. Homotopic grafts at the four-somite stage were allowed to survive for up to 9 days to enable an analysis of definitive brain structures. In some cases, the topography of the grafted neuroepithelia was compared with gene expression patterns. The midpoint of the anterior neural ridge maps upon the anterior commissure in the closed neural tube, continuing concentrically into the preoptic area and optic field. Non-neural epithelium just in front of this median ridge gives rise to the adenohypophysis. Areas for the presumptive pallial commissure, septum, and prosencephalic choroidal tissue lie progressively more posteriorly along the ridge, peripheral to the telencephalic entopeduncular and striatopallidal primordia (the subpallium), and the pallium (olfactory bulb, dorsal ventricular ridge, and cortical domains). Subpallial structures lie topologically anterior to the pallial formations, and both are concentric to the septum. Within the pallium, the major cortical domains (Wulst and caudolateral, parahippocampal, and hippocampal cortices) appear posterior to the dorsal ventricular ridge. The amygdaloid region appears concentrically across both the subpallial and pallial regions. This fate map shows that the arrangement of the prospective primordia in the neural plate is basically a flattened representation of topological relationships present in the mature brain, though marked phenomena of differential growth and selective tangential migration of some cell populations complicate the histogenetic constitution of the mature telencephalon.I.C. received a FPI Fellowship from Fundacion Seneca (Murcia). This work was supported by European Community contract ERB-FMRX-CT96-0065, Human Frontiers Science Program grant RG41-95, and Spanish CICYT grant PB98-0397 (to L.P.); Fundacion Seneca (Murcia) 708/CV/99, European Community contracts BIO4-98-0309, QLG2-99-00793, QLG3-2000-01556, and QLG3-2000-01625 (to S.M.); grants-in-aid from the Ministry of Education, Science, Sports, and Culture (to K.S.); Nina Ireland, Human Frontiers Science Program grant RG41-95, NIMH K02 MH01046-01 (to J.L.R.R.).Peer reviewe