Mouse Postnatal Development Research Articles

Three paternally imprinted regions are sequentially required in prenatal and postnatal mouse development.

Three paternally imprinted regions are sequentially required in prenatal and postnatal mouse development.

Inhibitory neurons in the right place

Neurodevelopment Disruption of γ-aminobutyric acid–mediated (GABAergic) interneuron migration is implicated in neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Su et al. found that dopamine induced the association of the dopamine receptor D1R with the guanosine triphosphatase–activating protein SynGAP. During embryonic and early postnatal development in mice, this complex promoted dopamine-induced migration of GABAergic interneurons but not glutamatergic interneurons. These findings may explain why mutations in SYNGAP1 give rise to neurodevelopmental disorders. Sci. Signal. 12 , eaau9122 (2019).

Adverse early-life environment impairs postnatal lung development in mice.

Fetal growth restriction (FGR) is a major risk factor for bronchopulmonary dysplasia (BPD). Maternal stress and poor diet are linked to FGR. Effect of perinatal stress on lung development remains unknown. Using a murine model of adverse early life environment (AELE), we hypothesized that maternal exposure to perinatal environmental stress and high-fat diet (Western diet) lead to impaired lung development in the offspring. Female mice were placed on either control diet or Western diet before conception. Those exposed to Western diet were also exposed to perinatal environmental stress, the combination referred to as AELE. Pups were either euthanized at postnatal day 21 (P21) or weaned to control diet and environment until adulthood (8-14 wk old). Lungs were harvested for histology, gene expression by quantitative RT-PCR, microRNA profiling, and immunoblotting. AELE increased the mean linear intercept and decreased the radial alveolar count and secondary septation in P21 and adult mice. Capillary count was also decreased in P21 and adult mice. AELE lungs had decreased vascular endothelial growth factor A (VEGFA), VEGF receptor 2, endothelial nitric oxide synthase, and hypoxia inducible factor-1α protein levels and increased expression of genes that regulate DNA methylation and upregulation of microRNAs that target genes involved in lung development at P21. AELE leads to impaired lung alveolar and vascular growth, which persists into adult age despite normalizing the diet and environment at P21. AELE also alters the expression of genes involved in lung remodeling.

Abstract 4405: Acetylation of KLF5 controls the cell fate of basal progenitors during postnatal development and regeneration of mouse prostates

Abstract Adult stem cells are responsible for lineage specification in epithelial homeostasis, and thus are essential for both postnatal development and tissue regeneration. Genetic changes in adult stem cells have been revealed to promote cancer development. Dissecting the underlying regulators is critical for understanding the intrinsic mechanisms that regulate adult stem cell function, yet whether PTM of a single molecule determines cell fate of adult stem cells during organ development has not been well established, particularly for glandular organs. Using the androgen-dependent mouse prostate as an experimental system, an ideal system for understanding epithelial hierarchy, we examined the Krüppel-like factor 5 (Klf5) transcription factor and its acetylation for their roles in postnatal development and regeneration. The absence of KLF5 eliminated basal progenitor activities in both human and mouse prostate epithelial cells, as indicated by a compromised sphere and organoid formatting capabilities, downregulation of basal cell markers, and decreased basal cells. Klf5 was also necessary for basal progenitor cells to maintain their luminal differentiation capacity, as loss of Klf5 also decreased basal progenitor-derived luminal cells and their proliferation in mouse prostates. Interestingly, the progenitor activity of Klf5 was restricted to deacetylated Klf5 (deAc-Klf5), as indicated by in vitro and in vivo assays. On the other hand, acetylated Klf5 (Ac-Klf5) was essential for proper formation and maintenance of luminal structures in mouse prostates, as deacetylation of Klf5 interrupted the formation of normal luminal structures, almost eliminated the castration resistance in basal progenitor-derived luminal cells, and attenuated the luminal regeneration after a castration-regeneration cycle, even though deAc-Klf5 promoted basal-to-luminal differentiation and the proliferation of luminal cells during postnatal development. Mechanistically, deacetylation of Klf5 increased Notch signaling activity. These findings indicate that Klf5 and its acetylation control the cell fate of prostatic basal progenitors, which have a distinct contribution to postnatal development and regeneration of the prostate. Considering that androgen deprivation therapy (ADT) is currently a major therapeutic strategy in the treatment of prostate cancer, our findings also provide a potential mechanism for prostate cancer progression, i.e., interruption of Klf5 acetylation could sensitize castration-resistant prostate cancer to ADT or slow the recurrence of prostate cancer after ADT. Citation Format: Baotong Zhang, Jin-Tang Dong. Acetylation of KLF5 controls the cell fate of basal progenitors during postnatal development and regeneration of mouse prostates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4405.

2158-P: GLIS3 Is Crucial for Maintenance of Neonatal ß Cells

The Krüpple-like zinc finger transcription factor, GLI-similar 3 (GLIS3), is critical for pancreatic β cell development and insulin production. Mutations and single nucleotide variants in the GLIS3 gene have been linked to the development of neonatal diabetes and increased risk of type 1 and 2 diabetes. Early during postnatal development pancreatic β cells proliferate and mature; however, little is known about the role of GLIS3 during this stage of β cell development. In this study, we examined the role of GLIS3 on gene expression in β cells during early mouse postnatal development. Immunohistochemistry, QRT-PCR, and transmission electron microscopy indicated that postnatal GLIS3KO islets still contain a large population of β cells that express PDX1, NKX6.1, and ISL-1; however, neonatal insulin production and insulin-secretory granules were greatly reduced in INSlowPDX1+NKX6.1+ cells. Gene expression profiling by RNA-Seq with islets from WT and GLIS3KO mouse and identification of GLIS3 target genes by ChIP-Seq analysis showed that GLIS3 directly regulates the expression of a number of genes involved in β cell function and maturation, including Insulin1 and 2 (Ins1, Ins2), Solute Carrier Family 2 member 2 and 1(Slc2a2, Slc2a1), Activating Transcription Factor 4 and 6b (Atf4, Atf6b), and MAF BZIP Transcription Factor A (MafA), and as well as the expression of a number of metabolic genes. Our study indicates that GLIS3 plays a critical role in the maturation and maintenance of pancreatic β cells during early postnatal development by directly regulating genes with key β cell functions. Disclosure H. Kang: None. D. Scoville: None. K. Jeon: None. S. Grimm: None. A.M. Jetten: None.

Cardiac fibroblast lineages and extracellular matrix maturation in postnatal heart development

During postnatal heart development in mice, the ventricular myocardium undergoes extensive remodeling with increased organization and maturation of cardiomyocytes, fibroblasts and endothelial cells. In addition, the extracellular matrix (ECM), consisting mostly of mature fibrillar collagen is produced, providing necessary mechanical support for increased cardiac output. In adult hearts, the matricellular protein periostin (postn) is induced during cardiac injury and is required for collagen deposition in scar formation and pathologic fibrosis. During postnatal heart remodeling, postn also is expressed in cardiac fibroblasts coincident with collagen 1a1 gene expression. At the same time, fibronectin expression indicative of immature ECM permissive for cardiomyocyte proliferation is decreased. By postnatal day 30, postn expression is decreased and the collagen‐rich ECM surrounding individual cardiomyocytes is apparent. The expression of postn during postnatal heart remodeling and ECM maturation supports shared molecular regulation of cardiac fibroblasts and collagen fibrillogenesis in development and disease. However, the specific contributions of postn‐expressing cardiac fibroblasts to the initial production of the collagen‐rich ECM of the heart or to maturation and hypertrophy of adjacent cardiomyocytes are not yet known.Support or Funding InformationThis work was supported by grants from the NIH/NHLBI (P01HL069779 and R01HL142217)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

An opsin 5-dopamine pathway mediates light-dependent vascular development in the eye.

During mouse postnatal eye development, the embryonic hyaloid vascular network regresses from the vitreous as an adaption for high acuity vision. This process occurs with precisely controlled timing. Here we show that an Opsin 5 (OPN5, Neuropsin)-dependent retinal light response regulates vascular development in the postnatal eye. In Opn5 null mice hyaloid vessels regress precociously. We demonstrate that 380 nm light stimulation via OPN5 and VGAT (the vesicular GABA/glycine transporter) in retinal ganglion cells enhances activity of inner retinal DAT/SLC6A3 (a dopamine reuptake transporter) and thus suppresses vitreal dopamine. In turn, dopamine acts directly on hyaloid vascular endothelial cells to suppress activity of VEGFR2 and promote hyaloid vessel regression. With OPN5 loss-of-function, vitreous dopamine is elevated and results in premature hyaloid regression. These investigations identify violet light as a developmental timing cue that, via an OPN5-dopamine pathway, regulates optic axis clearance in preparation for visual function.

Late-onset megaconial myopathy in mice lacking group I Paks

BackgroundGroup I Paks are serine/threonine kinases that function as major effectors of the small GTPases Rac1 and Cdc42, and they regulate cytoskeletal dynamics, cell polarity, and transcription. We previously demonstrated that Pak1 and Pak2 function redundantly to promote skeletal myoblast differentiation during postnatal development and regeneration in mice. However, the roles of Pak1 and Pak2 in adult muscle homeostasis are unknown. Choline kinase β (Chk β) is important for adult muscle homeostasis, as autosomal recessive mutations in CHKβ are associated with two human muscle diseases, megaconial congenital muscular dystrophy and proximal myopathy with focal depletion of mitochondria.MethodsWe analyzed mice conditionally lacking Pak1 and Pak2 in the skeletal muscle lineage (double knockout (dKO) mice) over 1 year of age. Muscle integrity in dKO mice was assessed with histological stains, immunofluorescence, electron microscopy, and western blotting. Assays for mitochondrial respiratory complex function were performed, as was mass spectrometric quantification of products of choline kinase. Mice and cultured myoblasts deficient for choline kinase β (Chk β) were analyzed for Pak1/2 phosphorylation.ResultsdKO mice developed an age-related myopathy. By 10 months of age, dKO mouse muscles displayed centrally-nucleated myofibers, fibrosis, and signs of degeneration. Disease severity occurred in a rostrocaudal gradient, hindlimbs more strongly affected than forelimbs. A distinctive feature of this myopathy was elongated and branched intermyofibrillar (megaconial) mitochondria, accompanied by focal mitochondrial depletion in the central region of the fiber. dKO muscles showed reduced mitochondrial respiratory complex I and II activity. These phenotypes resemble those of rmd mice, which lack Chkβ and are a model for human diseases associated with CHKβ deficiency. Pak1/2 and Chkβ activities were not interdependent in mouse skeletal muscle, suggesting a more complex relationship in regulation of mitochondria and muscle homeostasis.ConclusionsConditional loss of Pak1 and Pak2 in mice resulted in an age-dependent myopathy with similarity to mice and humans with CHKβ deficiency. Protein kinases are major regulators of most biological processes but few have been implicated in muscle maintenance or disease. Pak1/Pak2 dKO mice offer new insights into these processes.

Spatiotemporal regulation of multipotency during prostate development.

ABSTRACTThe prostate is formed by a branched glandular epithelium composed of basal cells (BCs) and luminal cells (LCs). Multipotent and unipotent stem cells (SCs) mediate the initial steps of prostate development whereas BCs and LCs are self-sustained in adult mice by unipotent lineage-restricted SCs. The spatiotemporal regulation of SC fate and the switch from multipotency to unipotency remain poorly characterised. Here, by combining lineage tracing, whole-tissue imaging, clonal analysis and proliferation kinetics, we uncover the cellular dynamics that orchestrate prostate postnatal development in mouse. We found that at an early stage of development multipotent basal SCs are located throughout the epithelium and are progressively restricted at the distal tip of the ducts, where, together with their progeny, they establish the different branches and the final structure of prostate. In contrast, pubertal development is mediated by unipotent lineage-restricted SCs. Our results uncover the spatiotemporal regulation of the switch from multipotency to unipotency during prostate development.

Groucho related gene 5 (GRG5) is involved in embryonic and neural stem cell state decisions

Groucho related gene 5 (GRG5) is a multifunctional protein that has been implicated in late embryonic and postnatal mouse development. Here, we describe a previously unknown role of GRG5 in early developmental stages by analyzing its function in stem cell fate decisions. By both loss and gain of function approaches we demonstrate that ablation of GRG5 deregulates the Embryonic Stem Cell (ESC) pluripotent state whereas its overexpression leads to enhanced self-renewal and acquisition of cancer cell-like properties. The malignant characteristics of teratomas generated by ESCs that overexpress GRG5 reveal its pro-oncogenic potential. Furthermore, transcriptomic analysis and cell differentiation approaches underline GRG5 as a multifaceted signaling regulator that represses mesendodermal-related genes. When ESCs exit pluripotency, GRG5 promotes neuroectodermal specification via Wnt and BMP signaling suppression. Moreover, GRG5 promotes the neuronal reprogramming of fibroblasts and maintains the self-renewal of Neural Stem Cells (NSCs) by sustaining the activity of Notch/Hes and Stat3 signaling pathways. In summary, our results demonstrate that GRG5 has pleiotropic roles in stem cell biology functioning as a stemness factor and a neural fate specifier.

The role of intragestational ghrelin on postnatal development and reproductive programming in mice

The purpose of this study was to evaluate the intragestational role of ghrelin in offspring development and reproductive programming in a mouse model of ghrelin imbalance during pregnancy. Female mice were injected with ghrelin (supraphysiological levels: 4 nmol/animal/day), antagonist (endogenous ghrelin inhibition with (D-Lys3)GHRP-6, 6 nmol/animal/day) or vehicle (control = normal ghrelin levels) throughout the pregnancy. Parameters evaluated in litters were growth, physical, neurobiological and sexual development and, at adulthood, reproductive function. Litter size and initial weight did not vary between treatments. Male pups from dams treated with ghrelin showed higher body weight increase until adulthood (31.7 ± 0.8 vs control = 29.7 ± 0.7, n = 11–14 litters/treatment; P < 0.05). Postnatal physical and neurobiological development was not modified by treatments. The antagonist accelerated male puberty onset, evidenced as earlier testis descent and increased relative testicular weight (antagonist = 0.5 ± 0.0% vs ghrelin = 0.4 ± 0.0% and control = 0.4 ± 0.0%, n = 5–10 litters/treatment; P < 0.05). At adulthood, these males exhibited lower relative testicular weight and reduced sperm motility (63.9 ± 3.6% vs control = 70.9 ± 3.3 and ghrelin = 75.6 ± 3.0, n = 13–15 animals; P < 0.05), without changes in plasma testosterone or fertility. Female pups intragestationally exposed to the antagonist showed earlier vaginal opening (statistically significant only at Day 25) and higher ovarian volume (antagonist = 1085.7 ± 64.0 mm3 vs ghrelin = 663.3 ± 102.8 mm3 and control = 512.3 ± 116.4 mm3; n = 4–6 animals/treatment; P < 0.05), indicating earlier sexual maturation. At adulthood, these females and those exposed to ghrelin showed a tendency to higher percentages of embryo loss and/or foetal atrophy. In conclusion, ghrelin participates in reproductive foetal programming: alterations in ghrelin activity during pregnancy modified body weight increase and anticipated puberty onset, exerting (or tending to) negative effects on adult reproductive function.

Low dose exposure to HBCD, CB-153 or TCDD induces histopathological and hormonal effects and changes in brain protein and gene expression in juvenile female BALB/c mice

Developmental health risks of chronical exposure to low doses of foodborne persistent organic pollutants (POP) are recognized but still largely uncharacterized. Juvenile female BALB/c mice exposed to either HBCD, CB-153 or TCDD at doses relevant to human dietary exposures (49.5 μg, 1.35 μg and 0.90 ng kg−1 bw−1 day−1, respectively) for 28 days displayed histopathological changes in liver (HBCD, CB-153, TCDD), thymus (HBCD, CB-153) and uterus (HBCD), reduced serum oestradiol 17β (E2) levels (HBCD), increased serum testosterone (T) levels (CB-153) and an increased T/E2 ratio (HBCD). Proteomics analysis of brain provided molecular support for the HBCD-induced reduction in E2. Neural gene expression analysis, confirmed effects on 18 out of 30 genes previously found to be affected after exposure to higher doses to the same pollutants. Our findings indicate that exposure to POP at low doses is associated with subtle, but toxicological relevant effects on post-natal development in female mice.

Nestin in the epididymis is expressed in vascular wall cells and is regulated during postnatal development and in case of testosterone deficiency.

Vascular smooth muscle cells (SMCs), distinguished by the expression of the neuronal stem cell marker nestin, may represent stem cell-like progenitor cells in various organs including the testis. We investigated epididymal tissues of adult nestin-GFP mice, rats after Leydig cell depletion via ethane dimethane sulfonate (EDS), rats and mice during postnatal development and human tissues. By use of Clarity, a histochemical method to illustrate a three-dimensional picture, we could demonstrate nestin-GFP positive cells within the vascular network. We localized nestin in the epididymis in proliferating vascular SMCs by colocalization with both smooth muscle actin and PCNA, and it was distinct from CD31-positive endothelial cells. The same nestin localization was found in the human epididymis. However, nestin was not found in SMCs of the epididymal duct. Nestin expression is high during postnatal development of mouse and rat and down-regulated towards adulthood when testosterone levels increase. Nestin increases dramatically in rats after Leydig cell ablation with EDS and subsequently low testosterone levels. Interestingly, during this period, the expression of androgen receptor in the epididymis is low and increases until nestin reaches normal levels of adulthood. Here we show that nestin, a common marker for neuronal stem cells, is also expressed in the vasculature of the epididymis. Our results give new insights into the yet underestimated role of proliferating nestin-expressing vascular SMCs during postnatal development and repair of the epididymis.

Prolactin regulates liver growth during postnatal development in mice.

The liver grows during the early postnatal period first at slower and then at faster rates than the body to achieve the adult liver-to-body weight ratio (LBW), a constant reflecting liver health. The hormone prolactin (PRL) stimulates adult liver growth and regeneration, and its levels are high in the circulation of newborn infants, but whether PRL plays a role in neonatal liver growth is unknown. Here, we show that the liver produces PRL and upregulates the PRL receptor in mice during the first 2 wk after birth, when liver growth lags behind body growth. At postnatal week 4, the production of PRL by the liver ceases coinciding with the elevation of circulating PRL and the faster liver growth that catches up with body growth. PRL receptor null mice ( Prlr-/-) show a significant decrease in the LBW at 1, 4, 6, and 10 postnatal weeks and reduced liver expression of proliferation [cyclin D1 ( Ccnd1)] and angiogenesis [platelet/endothelial cell adhesion molecule 1 ( Pecam1)] markers relative to Prlr+/+ mice. However, the LBW increases in Prlr-/- mice at postnatal week 2 concurring with the enhanced liver expression of Igf-1 and the liver upregulation and downregulation of suppressor of cytokine signaling 2 ( Socs2) and Socs3, respectively. These findings indicate that PRL acts locally and systemically to restrict and stimulate postnatal liver growth. PRL inhibits liver and body growth by attenuating growth hormone-induced Igf-1 liver expression via Socs2 and Socs3-related mechanisms.

Sexual dimorphism of microglia and synapses during mouse postnatal development.

ABSTRACTMicroglia participate in synapse remodeling in the cortex and hippocampus during mouse postnatal development. Although sex differences in microglia activity during embryonic development have been reported in these regions, it remains unexplored whether microglia show sexually dimorphic features during the early postnatal period, a critical window for synapse formation and maturation. Here, we investigated morphological and functional features of microglia across early postnatal development as well as morphological features of both pre‐ and postsynaptic neuronal compartments in the mouse hippocampus. We found a sex‐dependent shift in microglia volume and phagocytic capacity across the first four postnatal weeks. Measurements of synaptic features revealed sex differences in the density of synaptic spines and boutons during the second postnatal week. These data are consistent with a precocious development of both microglia and synapses in the female brain. We further hypothesize that this bias may contribute to sex‐specific brain wiring. © 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 78: 618–626, 2018

Regulation of Blood-Testis Barrier (BTB) Dynamics, Role of Actin-, and Microtubule-Based Cytoskeletons.

The blood-testis barrier (BTB) is an important ultrastructure in the testis that supports meiosis and postmeiotic spermatid development since a delay in the establishment of a functional Sertoli cell barrier during postnatal development in rats or mice by 17-20 day postpartum (dpp) would lead to a delay of the first wave of meiosis. Furthermore, irreversible disruption of the BTB by toxicants also induces infertility in rodents. Herein, we summarize recent findings that BTB dynamics (i.e., disassembly, reassembly, and stabilization) are supported by the concerted efforts of the actin- and microtubule (MT)-based cytoskeletons. We focus on the role of two actin nucleation protein complexes, namely, the Arp2/3 (actin-related protein 2/3) complex and formin 1 (or the formin 1/spire 1 complex) known to induce actin nucleation, respectively, by conferring plasticity to actin cytoskeleton. We also focus on the MT plus (+)-end tracking protein (+TIP) EB1 (end-binding protein 1) which is known to confer MT stabilization. Furthermore, we discuss in particular how the interactions of these proteins modulate BTB dynamics during spermatogenesis. These findings also yield a novel hypothetical concept regarding the molecular mechanism that modulates BTB function.

Global gene expression analysis combined with a genomics approach for the identification of signal transduction networks involved in postnatal mouse myocardial proliferation and development.

Mammalian cardiomyocytes may permanently lose their ability to proliferate after birth. Therefore, studying the proliferation and growth arrest of cardiomyocytes during the postnatal period may enhance the current understanding regarding this molecular mechanism. The present study identified the differentially expressed genes in hearts obtained from 24 h-old mice, which contain proliferative cardiomyocytes; 7-day-old mice, in which the cardiomyocytes are undergoing a proliferative burst; and 10-week-old mice, which contain growth-arrested cardiomyocytes, using global gene expression analysis. Furthermore, myocardial proliferation and growth arrest were analyzed from numerous perspectives, including Gene Ontology annotation, cluster analysis, pathway enrichment and network construction. The results of a Gene Ontology analysis indicated that, with increasing age, enriched gene function was not only associated with cell cycle, cell division and mitosis, but was also associated with metabolic processes and protein synthesis. In the pathway analysis, 'cell cycle', proliferation pathways, such as the 'PI3K-AKT signaling pathway', and 'metabolic pathways' were well represented. Notably, the cluster analysis revealed that bone morphogenetic protein (BMP)1, BMP10, cyclin E2, E2F transcription factor 1 and insulin like growth factor 1 exhibited increased expression in hearts obtained from 7-day-old mice. In addition, the signal transduction pathway associated with the cell cycle was identified. The present study primarily focused on genes with altered expression, including downregulated anaphase promoting complex subunit 1, cell division cycle (CDC20), cyclin dependent kinase 1, MYC proto-oncogene, bHLH transcription factor and CDC25C, and upregulated growth arrest and DNA damage inducible α in 10-week group, which may serve important roles in postnatal myocardial cell cycle arrest. In conclusion, these data may provide important information regarding myocardial proliferation and development.

Exposure to fine and ultrafine particulate matter during gestation alters postnatal oligodendrocyte maturation, proliferation capacity, and myelination

Accumulating studies indicate that the brain is a direct target of air pollution exposure during the fetal period. We have previously demonstrated that exposure to concentrated ambient particles (CAPs) during gestation produces ventriculomegaly, periventricular hypermyelination, and enlargement of the corpus callosum (CC) during postnatal development in mice. This study aimed to further characterize the cellular basis of the observed hypermyelination and determine if this outcome, among other effects, persisted as the brain matured. Analysis of CC-1+ mature oligodendrocytes in the CC at postnatal days (PNDs) 11–15 suggest a premature maturational shift in number and proportion of total cells in prenatally CAPs-exposed males and females, with no overall change in total CC cellularity. The overall number of Olig2+ lineage cells in the CC was not affected in either sex at the same postnatal timepoint. Assessment of myelin status at early brain maturity (PNDs 57–61) revealed persistent hypermyelination in CAPs-exposed animals of both sexes. In addition, ventriculomegaly was persistent in CAPs-treated females, with possible amelioration of ventriculomegaly in CAPs-exposed males. When oligodendrocyte precursor cell (OPC) pool status was analyzed at PNDs 57–61, there were significant CAPs-induced alterations in cycling Ki67+/Olig2+ cell number and proportion of total cells in the female CC. Total CC cellularity was slightly elevated in CAPs-exposed males at PNDs 57–61. Overall, these data support a growing body of evidence that demonstrate the vulnerability of the developing brain to environmental insults such as ambient particulate matter. The sensitivity of oligodendrocytes and myelin, in particular, to such an insult warrants further investigation into the mechanistic underpinnings of OPC and myelin disruption by constituent air pollutants.

Prenatal Exposure to Paint Thinner Alters Postnatal Development and Behavior in Mice.

Occupational exposure and sniffing of volatile organic solvents continue to be a worldwide health problem, raising the risk for teratogenic sequelae of maternal inhalant abuse. Real life exposures usually involve simultaneous exposures to multiple solvents, and almost all the abused solvents contain a mixture of two or more different volatile compounds. However, several studies examined the teratogenicity due to industrial exposure to a single volatile solvent but investigating the teratogenic potential of complex chemical mixture such as thinner remains unexplored. This study was undertaken to evaluate developmental neurotoxicity of paint thinner using a mouse model. Mated female mice (N = 21) were, therefore, exposed to repeated and brief inhalation episodes of 0, 300 or 600 ppm of thinner during the entire period of pregnancy. Females weigh was recorded and their standard fertility and reproductive parameters were assessed. After birth postnatal day 1 (PND1), offspring (N = 88) length and body weight were measured in a daily basis. At PND5, the pups were assessed for their postnatal growth, physical maturation, reflex development, neuromotor abilities, sensory function, activity level, anxiety, depression, learning and memory functions. At adulthood, structural changes of the hippocampus were examined by estimating the total volume of the dentate gyrus. Except one case of thinner induced abortion at the higher dose, our results showed that the prenatal exposure to the solvent did not cause any maternal toxicity or decrease in the viability of the offspring. Therefore, a lower birth weight, decrease in the litter size and delayed reflexes ontogeny were registered in prenatally exposed offspring to both 300 ppm and 600 ppm of thinner. In addition, prenatally exposure to thinner resulted in increased anxiolytic- and depression-like behaviors. In contrast, impaired learning and memory functions and decreased hippocampal dentate gyrus volume were revealed only in the prenatally treated offspring by 600 ppm of thinner. Based on these results, we can conclude that prenatally exposure to paint thinner causes a long-lasting developmental neurotoxicity and alters a wide range of behavioral functions in mice. This shows the risk that mothers who abuse thinner paint expose their offspring.

The Impact of the Eda Pathway on Tooth Root Development

The Eda pathway (Eda, Edar, Edaradd) plays an important role in tooth development, determining tooth number, crown shape, and enamel formation. Here we show that the Eda pathway also plays a key role in root development. Edar (the receptor) is expressed in Hertwig’s epithelial root sheath (HERS) during root development, with mutant mice showing a high incidence of taurodontism: large pulp chambers lacking or showing delayed bifurcation or trifurcation of the roots. The mouse upper second molars in the Eda pathway mutants show the highest incidence of taurodontism, this enhanced susceptibility being matched in human patients with mutations in EDA-A1. These taurodont teeth form due to defects in the direction of extension of the HERS from the crown, associated with a more extensive area of proliferation of the neighboring root mesenchyme. In those teeth where the angle at which the HERS extends from the crown is very wide and therefore more vertical, the mutant HERSs fail to reach toward the center of the tooth in the normal furcation region, and taurodont teeth are created. The phenotype is variable, however, with milder changes in angle and proliferation leading to normal or delayed furcation. This is the first analysis of the role of Eda in the root, showing a direct role for this pathway during postnatal mouse development, and it suggests that changes in proliferation and angle of HERS may underlie taurodontism in a range of syndromes.