Extensive migration of young neurons into the infant human frontal lobe.

The first few months after birth, when a child begins to interact with the environment, are critical to human brain development. The human frontal lobe is important for social behavior and executive function; it has increased in size and complexity relative to other species, but the processes that have contributed to this expansion are unknown. Our studies of postmortem infant human brains revealed a collection of neurons that migrate and integrate widely into the frontal lobe during infancy. Chains of young neurons move tangentially close to the walls of the lateral ventricles and along blood vessels. These cells then individually disperse long distances to reach cortical tissue, where they differentiate and contribute to inhibitory circuits. Late-arriving interneurons could contribute to developmental plasticity, and the disruption of their postnatal migration or differentiation may underlie neurodevelopmental disorders

The LIM Homeodomain Factor Lhx2 Is Required for Hypothalamic Tanycyte Specification and Differentiation

Hypothalamic tanycytes, a radial glial-like ependymal cell population that expresses numerous genes selectively enriched in embryonic hypothalamic progenitors and adult neural stem cells, have recently been observed to serve as a source of adult-born neurons in the mammalian brain. The genetic mechanisms that regulate the specification and maintenance of tanycyte identity are unknown, but are critical for understanding how these cells can act as adult neural progenitor cells. We observe that LIM (Lin-11, Isl-1, Mec-3)-homeodomain gene Lhx2 is selectively expressed in hypothalamic progenitor cells and tanycytes. To test the function of Lhx2 in tanycyte development, we used an intersectional genetic strategy to conditionally delete Lhx2 in posteroventral hypothalamic neuroepithelium, both embryonically and postnatally. We observed that tanycyte development was severely disrupted when Lhx2 function was ablated during embryonic development. Lhx2-deficient tanycytes lost expression of tanycyte-specific genes, such as Rax, while also displaying ectopic expression of genes specific to cuboid ependymal cells, such as Rarres2. Ultrastructural analysis revealed that mutant tanycytes exhibited a hybrid identity, retaining radial morphology while becoming multiciliated. In contrast, postnatal loss of function of Lhx2 resulted only in loss of expression of tanycyte-specific genes. Using chromatin immunoprecipitation, we further showed that Lhx2 directly regulated expression of Rax, an essential homeodomain factor for tanycyte development. This study identifies Lhx2 as a key intrinsic regulator of tanycyte differentiation, sustaining Rax-dependent activation of tanycyte-specific genes while also inhibiting expression of ependymal cell-specific genes. These findings provide key insights into the transcriptional regulatory network specifying this still poorly characterized cell type

Exposure to N-Ethyl-N-Nitrosourea in Adult Mice Alters Structural and Functional Integrity of Neurogenic Sites

BACKGROUND: Previous studies have shown that prenatal exposure to the mutagen N-ethyl-N-nitrosourea (ENU), a N-nitroso compound (NOC) found in the environment, disrupts developmental neurogenesis and alters memory formation. Previously, we showed that postnatal ENU treatment induced lasting deficits in proliferation of neural progenitors in the subventricular zone (SVZ), the main neurogenic region in the adult mouse brain. The present study is aimed to examine, in mice exposed to ENU, both the structural features of adult neurogenic sites, incorporating the dentate gyrus (DG), and the behavioral performance in tasks sensitive to manipulations of adult neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: 2-month old mice received 5 doses of ENU and were sacrificed 45 days after treatment. Then, an ultrastructural analysis of the SVZ and DG was performed to determine cellular composition in these regions, confirming a significant alteration. After bromodeoxyuridine injections, an S-phase exogenous marker, the immunohistochemical analysis revealed a deficit in proliferation and a decreased recruitment of newly generated cells in neurogenic areas of ENU-treated animals. Behavioral effects were also detected after ENU-exposure, observing impairment in odor discrimination task (habituation-dishabituation test) and a deficit in spatial memory (Barnes maze performance), two functions primarily related to the SVZ and the DG regions, respectively. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that postnatal exposure to ENU produces severe disruption of adult neurogenesis in the SVZ and DG, as well as strong behavioral impairments. These findings highlight the potential risk of environmental NOC-exposure for the development of neural and behavioral deficits

Progressive Demyelination in the Presence of Serum Myelin Oligodendrocyte Glycoprotein-IgG: A Case Report

The clinical diagnosis of patients with autoantibodies directed to conformational myelin oligodendrocyte glycoprotein MOG-IgG, can be challenging because of atypical clinical presentation. MOG-IgG seropositivity has been reported in several demyelinating diseases, including relapsing opticospinal syndromes [in the neuromyelitis optica spectrum disorders (NMOSD) and less frequently, in multiple sclerosis (MS)], but it has rarely been associated with the progressive course of disease. To contribute to the characterization of MOG-related demyelination, we describe the case of a patient with progressive demyelinating opticospinal disease, IgG-oligoclonal bands (OCB), and serum MOG-IgG

Bi- and uniciliated ependymal cells define continuous floor-plate-derived tanycytic territories

Multiciliated ependymal (E1) cells line the brain ventricles and are essential for brain homeostasis. We previously identified in the lateral ventricles a rare ependymal subpopulation (E2) with only two cilia and unique basal bodies. Here we show that E2 cells form a distinct biciliated epithelium extending along the ventral third into the fourth ventricle. In the third ventricle floor, apical profiles with only primary cilia define an additional uniciliated (E3) epithelium. E2 and E3 cells\u27 ultrastructure, marker expression and basal processes indicate that they correspond to subtypes of tanycytes. Using sonic hedgehog lineage tracing, we show that the third and fourth ventricle E2 and E3 epithelia originate from the anterior floor plate. E2 and E3 cells complete their differentiation 2-3 weeks after birth, suggesting a link to postnatal maturation. These data reveal discrete bands of E2 and E3 cells that may relay information from the CSF to underlying neural circuits along the ventral midline

Evaluation of GAPS to Dcx expression in the DG of control and ENU animals.

<p>*<i>p</i><0.01.</p

Ultrastructural characterization of the SVZ from ENU-treated animals.

<p>The SVZ of treated animals was altered after ENU-exposure. (A) The type A cells located in the dorsal horn of the SVZ in ENU animals were drastically reduced, and substituted by astrocytic expansions. (B) High magnification of the SVZ dorsal horn with expansions rich in intermediate filaments (asterisks) in ENU animals. (C) Ependymal cell and neuroblasts frequently presented direct contact (arrow heads) in SVZ of treated animals. (D) Synaptic contacts located next to ependymal cell in animals exposed to ENU. (E) Large portions of basal membranes were observed between ependymal cells (arrows). (F) Myelinated and unmyelynated axons (arrows) were located between type A cells that composed chains, in ENU animals. Lv: lateral ventricle. Scale bar: A,F 10 µm, B 500 nm, C–E 2 µm.</p

ENU treatment impairs olfactory discrimination.

<p>During the habituation-dishabituation test a cotton swab was repeatedly presented to the mice above a target area and changed every minute. Exploration of the target area was examined. After 5 presentations without odorant, the swab was impregnated with an odorant (Odor A), and presented 6 times. Then, another swab was impregnated with a different odorant, (Odor B), which was also presented 6 times. The dotted lines represent the 1 min bins of exploration time of the target area. Notice that both groups similarly detected Odor A (last No Odor presentation Vs first Odor A presentation; * <i>p</i><0.01 for ENU-treated group; # <i>p</i><0.01 for control group), but when Odor B was presented only control animals discriminated the odor difference, responding to the new stimulus (last Odor A presentation Vs first Odor B presentation; # <i>p</i><0.01).</p

Decrease in proliferation after ENU-exposure as decrease in BrdU immunostaining.

<p>Micrograph of the BrdU+ cells immunolabeled with DAB showed a decrease in the proliferation in the SVZ (B) and DG (D) of treated animals, compared with control group (A and C, respectively). Delimited areas in C and D images are enlarged as C′ and D′, respectively, showing a detail of BrdU+ cells in DG. Scale bar: A 50 µm, C 100 µm.</p