Early Prenatal Stages Research Articles

Morphometrical Studies on the Exterior of the Heart of Pre-natal Non-descript Sheep

Background: Heart is the principal organ of circulatory system that pumps blood into the blood vessels and performs many vital functions. Its development before birth must be studied to safeguard the animal from the occurrence and consequences of various developmental anomalies. The detailed morphometry of different external parameters of heart especially in pre-natal sheep has not yet been reported.Methods: The foeti of sheep were divided into three age groups viz. early prenatal (up to 50 days), mid prenatal (51-100 days) and late prenatal (101 to 150 days) with fifteen animals in each age group. The various external parameters were recorded by using digital weighing machine, graduated measuring cylinder, digital Vernier’s calliper, non-stretchable nylon thread and graduated scale. The data recorded was statistically analysed by one way ANOVA with IBM SPSS 25.0 version software. Result: It was revealed that the average width of heart at its base was 4.82±0.22mm, 10.52±0.72mm and 21.57±1.03mm in early prenatal, mid prenatal and late prenatal stages respectively. The average dorso-ventral length of left ventricle of heart was measured as 4.82±0.14mm, 12.07±1.16mm and 25.58±0.88mm in early prenatal, mid prenatal and late prenatal stages respectively. The average distance between the left longitudinal groove and cranial border of heart at base was measured as 2.93±0.11mm, 6.38±0.39mm and 9.78±0.41mm in early prenatal, mid prenatal and late prenatal stages respectively. Similarly, the average distance between the right longitudinal groove and cranial border of heart at middle was measured as 1.96±0.09mm, 5.01±0.34mm and 8.31±0.50mm in early prenatal, mid prenatal and late prenatal stages respectively. All these parameters recorded showed significant (p ≤ 0.01) differences among the ages.

Signalling Pathways Implicated in Alzheimer's Disease Neurodegeneration in Individuals with and without Down Syndrome.

Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer’s disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.

Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals

BackgroundAutism is a heterogeneous collection of disorders with a complex molecular underpinning. Evidence from postmortem brain studies have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from individuals with autism with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism. MethodsiPSCs were generated from 9 unrelated individuals with autism without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing control individuals. iPSCs were differentiated toward either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterize iPSCs at different stages of differentiation. ResultsA subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to postmortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated toward a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs. ConclusionsTaken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.

Dynamics of cortical progenitors and production of subcerebral neurons are altered in embryos of a maternal inflammation model for autism.

The broad impairments in cognitive and neurologic functioning found in Autism Spectrum Disorder (ASD) patients are thought to originate during early prenatal developmental stages. Indeed, postmortem and imaging studies in ASD patients detected white-matter abnormalities, as well as prefrontal and temporal cortex deficits, evident from early childhood. Here, we used Maternal Immune Activation (MIA), a mouse model for ASD, in which the offsprings exhibit Autistic-like behaviors as well as cortical abnormalities. However, the dynamics that influence the number and the identity of newly born cortical neurons following maternal inflammation remains unknown. Our study shows early changes in the duration of the S-phase of PAX6+ progenitors, leading to an increased proportion of neurogenic divisions and a reciprocal decrease in the proliferative divisions. In two different time points of maternal inflammation, MIA resulted in an overproduction of CTIP2+ cortical neurons, which remained overrepresented at the end of gestation and in postnatal mice. Interestingly, MIA-resistant IL6-KO mice did not exhibit these changes. Lastly, we propose that elevated levels of the transcription factor PAX6 following MIA supports the overproduction of CTIP2+ neurons. Taken together, our data reveals a possible link between maternal immune activation and the excess of cortical neurons found in the cortex of ASD patients.

A de novo pathogenic CSNK1E mutation identified by exome sequencing in family trios with epileptic encephalopathy

Recent whole-exome sequencing (WES) studies have demonstrated the contribution of de novo mutations (DNMs) to epileptic encephalopathies (EEs). Here, we performed WES on four trios with West syndrome and identified three loss-of-function DNMs in both CSNK1E (c.885+1G>A) and STXBP1 (splicing, c.1111-2A>G; nonsense, p.(Y519X)). The splicing mutation in CSNK1E creates insertion of 116 new amino acids at position 246 followed by a premature stop codon. Both CSNK1E and STXBP1 showed a closer coexpression relationship with epilepsy candidate genes beyond that expected by chance. In addition, genes coexpressed with CSNK1E were enriched in early prenatal stages across multiple brain regions. We also found that 60 CSNK1E-interacting genes share an association with multiple neuropsychiatric disorders, and these genes formed a significant interconnected interaction network with roles in the midbrain development. Our study supported the potential role of CSNK1E variants in EE susceptibility and expanded the phenotypic spectrum associated with CSNK1E variation.

Lysosomal Cathepsin Protease Gene Expression Profiles in the Human Brain During Normal Development.

Cathepsin protease genes are necessary for protein homeostasis in normal brain development and function. The diversity of the 15 cathepsin protease activities raises the question of what are the human brain expression profiles of the cathepsin genes during development from prenatal and infancy to childhood, adolescence, and young adult stages. This study, therefore, evaluated the cathepsin gene expression profiles in 16 human brain regions during development by quantitative RNA-sequencing data obtained from the Allen Brain Atlas resource. Total expression of all cathepsin genes was the lowest at the early prenatal stage which became increased at the infancy stage. During infancy to young adult phases, total gene expression was similar. Interestingly, the rank ordering of gene expression among the cathepsins was similar throughout the brain at the age periods examined, showing (a) high expression of cathepsins B, D, and F; (b) moderate expression of cathepsins A, L, and Z; (c) low expression of cathepsins C, H, K, O, S, and V; and (d) very low expression of cathepsins E, G, and W. Results show that the human brain utilizes well-defined, balanced patterns of cathepsin gene expression throughout the different stages of human brain development. Knowledge gained by this study of the gene expression profiles of lysosomal cathepsin proteases among human brain regions during normal development is important for advancing future investigations of how these cathepsins are dysregulated in lysosomal-related brain disorders that affect infants, children, adolescents, and young adults.

Epiphyseal growth plate architecture is unaffected by early postnatal activation of the expression of R992C collagen II mutant.

Spondyloepiphyseal dysplasia (SED) exemplifies a group of heritable diseases caused by mutations in collagenous proteins of the skeletal system. Its main feature is altered skeletal growth. Pathomechanisms of SED include: changes in the stability of collagen II molecules, inability to form proper collagen fibrils, excessive intracellular retention of mutant molecules, and endoplasmic reticulum stress. The complexity of this pathomechanism presents a challenge for designing therapies for SED. Our earlier research tested whether such therapies only succeed when applied during a limited window of development. Here, employing an inducible mouse model of SED caused by the R992C mutation in collagen II, we corroborate our earlier observations that a therapy must be applied at the prenatal or early postnatal stages of skeletal growth in order to be successful. Moreover, we demonstrate that blocking the expression of the R992C collagen II mutant at the early prenatal stages leads to long-term positive effects. Although, we could not precisely mark the start of the expression of the mutant, these effects are not significantly changed by switching on the mutant production at the early postnatal stages. By demonstrating the need for early therapeutic interventions, our study provides, for the first time, empirically-based directions for designing effective therapies for SED and, quite likely, for other skeletal dysplasias caused by mutations in key macromolecules of the skeletal system.

Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain.

Background: During early prenatal stages of brain development, serotonin (5-HT)-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR), innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13) has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system.Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency.Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs), which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5.Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell density of the developing DR and the posterior innervation of the prefrontal cortex (PFC), and therefore might be involved in the migration, axonal outgrowth and terminal target finding of DR 5-HT neurons. Dysregulation of CDH13 expression may thus contribute to alterations in this system of neurotransmission, impacting cognitive function, which is frequently impaired in neurodevelopmental disorders including attention-deficit/hyperactivity and autism spectrum disorders.

GATA1 Gene Polymorphisms in Down Syndrome Patients

Objectives: Down syndrome (DS) patients have a 500 fold higher possibility of developing acute megakaryoblastic leukemia (AMKL), compared with the general population. GATA1 mutations, acquired in the early prenatal stages, contributes to leukemogenesis in AMKL and has been the explanation for the cause of early hematopoietic disorders. The aim of this study was to investigate the influence of GATA1 gene polymorphisms in patients with DS. Methods: Thirty-nine DS patients, aged ≤ 4 years, were recruited into the study. GATA1 gene polymorphisms were identified by unidirectional deep sequencing. Results: GATA1 gene polymorphisms were identified in four patients: proband-11 had GATA1 gene polymorphism, NP_002040.1:p.His71Arg (rs374300356); proband-17 had NP_002040.1:p. Tyr69Cys; proband-19 had NP_002040.1:p.Lys100Arg; and proband-20 had NP_002040.1:p. Tyr69Cys. Analyzing these GATA1 gene polymorphisms with 14 different software programs to evaluate its pathogenicity showed that NP_002040.1:p.His71Arg had damaging effects on GATA1 gene function. Conclusion: We identified four GATA1 gene polymorphisms in this cohort of 39 patients. The polymorphism identified in proband-11 (NP_002040.1:p.His71Arg) has possible damaging effects on gene regulation, and thus, we recommend routine clinical examination in this patient.

Prospects and limitations of improving skeletal growth in a mouse model of spondyloepiphyseal dysplasia caused by R992C (p.R1192C) substitution in collagen II.

Skeletal dysplasias form a group of skeletal disorders caused by mutations in macromolecules of cartilage and bone. The severity of skeletal dysplasias ranges from precocious arthropathy to perinatal lethality. Although the pathomechanisms of these disorders are generally well defined, the feasibility of repairing established aberrant skeletal tissues that developed in the presence of mutant molecules is currently unknown. Here, we employed a validated mouse model of spondyloepiphyseal dysplasia (SED) that enables temporal control of the production of the R992C (p.R1192C) collagen II mutant that causes this disease. Although in our earlier studies we determined that blocking the expression of this mutant at the early prenatal stages prevents a SED phenotype, the utility of blocking the R992C collagen II at the postnatal stages is not known. Here, by switching off the expression of R992C collagen II at various postnatal stages of skeletal development, we determined that significant improvements of cartilage and bone morphology were achieved only when blocking the production of the mutant molecules was initiated in newborn mice. Our study indicates that future therapies of skeletal dysplasias may require defining a specific time window when interventions should be applied to be successful.

In utero exposure to fluoride and cognitive development delay in infants

The objective of this study was to evaluate the association between in utero exposure to fluoride (F) and Mental and Psychomotor Development (MDI and PDI) evaluated through the Bayley Scale of Infant Development II (BSDI-II) in infants. The sample included 65 mother-infant pairs. Environmental exposure to F was quantified in tap and bottled water samples and F in maternal urine was the biological exposure indicator; samples were collected during the 1st, 2nd and 3rd trimester of pregnancy. The mean values of F in tap water for the 1st, 2nd and 3rd trimester were 2.6±1.1mg/l, 3.1±1.1mg/l and 3.7±1.0mg/l respectively; above to 80% of the samples exceeded the reference value of 1.5mg/l (NOM-127-SSA1-1994). Regarding F in maternal urine, mean values were 1.9±1.0mg/l, 2.0±1.1mg/l and 2.7±1.1mg/l for the 1st, 2nd and 3rd trimester respectively. The infants with MDI and PDI scores less than 85 points were 38.5% and 20.9% respectively. After adjusting for potential confounding factors (gestational age, age of child, marginalization index and type of water for consumption), the MDI showed an inverse association with F levels in maternal urine for the first (β=−19.05, p=0.04) and second trimester (β=−19.34, p=0.01). Our data suggests that cognitive alterations in children born from exposed mothers to F could start in early prenatal stages of life.

In silico analysis of histone H3 gene expression during human brain development.

Precise regulation of chromatin structure is essential for proper development of higher eukaryotes, and methylation of histone H3 at lysine-27 (H3K27) by the Polycomb Repressive Complex 2 (PRC2) component EZH2 has emerged as an important and conserved mechanism to ensure silencing of developmentally regulated genes. Recurrent mutations within the histone H3 genes H3F3A and HIST1H3B that convert K27 to methionine (H3K27M) and disrupt the global H3K27 methylation landscape and PRC2-dependent silencing, have recently been identified in pediatric high-grade gliomas including Diffuse Intrinsic Pontine Glioma (DIPG) and Glioblastoma multiforme (GBM; Type IV glioma). These findings have generated renewed interest in the dynamics of histone genes and their expression, which have been difficult to study due to redundancy and high sequence homology within the H3 gene family. In this in silico study, we re-evaluated genomic organization of the human H3 gene family and expression of these genes in the human brain, utilizing public RNA-based sequence datasets for the human genome and brain development. We identified transcriptional activity from at least 17 protein-encoding H3 genes in the developing brain, comprising at least 14 canonical (H3.1)-like and 3 'replication-independent' (H3.3)-like forms, and encoding six distinct H3 isoforms. Transcripts for H3.3 genes including H3F3A show gradual decrease in abundance associated with developmental progression, whereas H3.1 transcripts including HIST1H3B tend to be strongly downregulated at an early prenatal stage and remain essentially silent thereafter. Twelve genes, including members of both H3.1 and H3.3 classes, contain a K27-AAG codon that is mutable to that for M (ATG), whereas the remaining contain the alternative, AAA codon for K at this position. H3F3A is the only H3.3-like gene containing the K27-AAG codon, whereas HIST1H3B is among ten H3.1-like genes containing this codon. This data indicates that, in the early developing human brain, HIST1H3B constitutes the largest proportion of H3.1 transcripts among H3.1 isoforms. We suggest that the apparent overrepresentation of K27M mutations in H3F3A relative to other H3 isoforms may result from its uniqueness among H3.3s for the K27-AAG codon and the functional relationship between H3.3 and PRC2, whereas overrepresentation of K27M mutations in HIST1H3B may be a product of strong relative expression of this gene in the early developing brain.

Therapeutic Angiogenesis in Ischemic Tissues by Growth Factors and Bone Marrow Mononuclear Cells Administration: Biological Foundation and Clinical Prospects.

The processes of new vessels formation in tissues are supported by two definite mechanisms: de novo development of blood vessels (vasculogenesis) through the accumulation of progenitor cells during early prenatal stage, and extension of a pre-existing microcirculatory network by endothelial cell germination (angiogenesis), the essential mechanism of blood vessel formation in postnatal period. Angiogenesis is associated with a series of inductive, permissive and restrictive communications that result in the appearance, differentiation, and formation of new vessels. The goal of therapeutic angiogenesis is to improve blood circulation, relay survival factors and regenerative stem cell populations to sites of tissue repair, and ultimately recover function and form of the tissue. Growth factors and bone marrow mononuclear cells represent a very interesting research field for the realization of therapeutic angiogenesis in ischemic tissues. They provide a potential key component in the healing processes of ischemic injured tissues.

Mapping the global mRNA transcriptome during development of the murine first molar.

The main objective of this study was to map global gene expression in order to provide information about the populations of mRNA species participating in murine tooth development at 24 h intervals, starting at the 11th embryonic day (E11.5) up to the 7th post-natal day (P7). The levels of RNA species expressed during murine tooth development were mesured using a total of 58 deoxyoligonucleotide microarrays. Microarray data was validated using real-time RT-PCR. Differentially expressed genes (p < 0.05) were subjected to bioinformatic analysis to identify cellular activities significantly associated with these genes. Using ANOVA the microarray data yielded 4362 genes as being differentially expressed from the 11th embryonic day (E11.5) up to 7 days post-natal (P7), 1921 of these being genes without known functions. The remaining 2441 genes were subjected to further statistical analysis using a supervised procedure. Bioinformatic analysis results for each time-point studied suggests that the main molecular functions associated with genes expressed at the early pre-natal stages (E12.5–E18.5) were cell cycle progression, cell morphology, lipid metabolism, cellular growth, proliferation, senescence and apoptosis, whereas most genes expressed at post-natal and secretory stages (P0–P7) were significantly associated with regulation of cell migration, biosynthesis, differentiation, oxidative stress, polarization and cell death. Differentially expressed genes (DE) not described earlier during murine tooth development; Inositol 1, 4, 5-triphosphate receptor 3 (Itpr3), metallothionein 1(Mt1), cyclin-dependent kinase 4 (Cdk4), cathepsin D (Ctsd), keratin complex 2, basic, gene 6a (Krt2-6a), cofilin 1, non-muscle (Cfl1), cyclin 2 (Ccnd2), were verified by real-time RT-PCR.

Directions for LD Treatment with Reflex Therapy

Increasing number of children with learning difficulties is a nationwide problem that requires immediate attention apart from neurobiology sciences, psychology, pedagogy, medicine, etc.. Children with learning disorders, ADHD, dyslexia, hypo / hyper tonic, autistic, hyperactive, language disorders, oral retention, coordination disorders, sensory disorders, emotional disorders and various other neural developments are known to maintain reflexes that have contributed to their symptoms and level of dysfunction. Difficulty in learning, from the presence of the initial reflexes beyond biological, Babinski, Moro and Startle, Walk or Steps (Stepping), Research (Rooting), feeding (sucking), Asymmetric Tonic Neck Reflex (ATNR), Tonic Reflex Maze (TLR), Palm Reflex (Palmar) Plantar Reflex (Plantar) Galant Reflex, such as parachute reflexes and abou 70 as these are neurological disorders and children may have difficulty speaking, reading, and/or writing, spelling, reasoning, perceiving, memorizing, organization and processing information. Primitive reflexes are essential for the survival and development in the womb and in the first months of life. Times of occurrence that initial reflexes begin are in early prenatal stages of the child in the uterus. Some initial reflexes are present at birth and are an indicator of development neurobiology. By anatomical and biological perspectives, initial reflexes stay for a short period of time and under the influence of specific movements, they refrain and postural reflexes take place. This is the stage when they are integrated with the higher centers of the brain control. If they are kept beyond their normal age of integration they can disturb some or all the functions of the higher brain centers which includes behavior; such as learning and integration of large or fine movements and more neurological disorders. Initial stem reflexes use a program based on the theory of repetition which enables alliteration of specific stages of development through paraphrasing movement patterns based on early brain development. The brain is given a "second chance" to pass through the stages which have been missing or have been incomplete movements in the first year of life, so therefor, nerves and nerve development pass in the proper time. DOI: 10.5901/ajis.2013.v2n11p77

Visual callosal topography in the absence of retinal input

Using probabilistic diffusion tractography, we examined the retinotopic organization of splenial callosal connections within early blind, anophthalmic, and control subjects. Early blind subjects experienced prenatal retinal “waves” of spontaneous activity similar to those of sighted subjects, and only lack postnatal visual experience. In anophthalmia, the eye is either absent or arrested at an early prenatal stage, depriving these subjects of both pre- and postnatal visual input. Therefore, comparing these two groups provides a way of separating the influence of pre- and postnatal retinal input on the organization of visual connections across hemispheres. We found that retinotopic mapping within the splenium was not measurably disrupted in early blind or anophthalmic subjects compared to visually normal controls. No significant differences in splenial volume were observed across groups. No significant differences in diffusivity were found between early blind subjects and sighted controls, though some differences in diffusivity were noted between anophthalmic subjects and controls. These results suggest that neither prenatal retinal activity nor postnatal visual experience plays a role in the large-scale topographic organization of visual callosal connections within the splenium.

Developmental Analysis and Influence of Genetic Background on the Lhx3 W227ter Mouse Model of Combined Pituitary Hormone Deficiency Disease

Combined pituitary hormone deficiency (CPHD) diseases result in severe outcomes for patients including short stature, developmental delays, and reproductive deficiencies. Little is known about their etiology, especially the developmental profiles and the influences of genetic background on disease progression. Animal models for CPHD provide valuable tools to investigate disease mechanisms and inform diagnostic and treatment protocols. Here we examined hormone production during pituitary development and the influence of genetic background on phenotypic severity in the Lhx3(W227ter/W227ter) mouse model. Lhx3(W227ter/W227ter) embryos have deficiencies of ACTH, α-glycoprotein subunit, GH, PRL, TSHβ, and LHβ during prenatal development. Furthermore, mutant mice have significant reduction in the critical pituitary transcriptional activator-1 (PIT1). Through breeding, the Lhx3(W227ter/W227ter) genotype was placed onto the 129/Sv and C57BL/6 backgrounds. Intriguingly, the genetic background significantly affected viability: whereas Lhx3(W227ter/W227ter) animals were found in the expected frequencies in C57BL/6, homozygous animals were not viable in the 129/Sv genetic environment. The hormone marker and PIT1 reductions observed in Lhx3(W227ter/W227ter) mice on a mixed background were also seen in the separate strains but in some cases were more severe in 129/Sv. To further characterize the molecular changes in diseased mice, we conducted a quantitative proteomic analysis of pituitary proteins. This showed significantly lower levels of PRL, pro-opiomelanocortin (ACTH), and α-glycoprotein subunit proteins in Lhx3(W227ter/W227ter) mice. Together, these data show that hormone deficiency disease is apparent in early prenatal stages in this CPHD model system. Furthermore, as is noted in human disease, genetic background significantly impacts the phenotypic outcome of these monogenic endocrine diseases.

Developmental Assessment

Developmental Assessment

Developmental Assessment

Developmental Assessment

Distribution patterns of estrogen receptor α and β in the human cortex and hippocampus during development and adulthood

The expression of estrogen receptors (ERs) in the developing and adult human brain has not been clearly established, although estrogens are crucial for neuronal differentiation, synapse formation, and cognitive functions. By using immunohistochemistry, we have studied the distribution of ER alpha and ER beta in human cerebral cortex and hippocampus from early prenatal stages to adult life. ER alpha was detected in the cortex at 9 gestational weeks (GW), with a high expression in proliferating zones and the cortical plate. The staining intensity decreased gradually during prenatal development but increased again from birth to adulthood. In contrast, ER beta was first detected at 15 GW in proliferating zones, and at 16/17 GW, numerous ER beta immunopositive cells were also observed in the cortical plate. ER beta expression persisted in the adult cortex, being widely distributed throughout cortical layers II-VI. In addition, from around 15 GW to adulthood, ER alpha and ER beta were expressed in human hippocampus mainly in pyramidal cells of Ammon's horn and in the dentate gyrus. Western blotting and immunohistochemistry in the adult cerebral cortex and hippocampus revealed lower protein expression of ER alpha compared with ER beta. Double immunostaining showed that during fetal life both ERs are expressed in neurons as well as in radial glia, although only ER alpha is expressed in the Cajal-Retzius neurons of the marginal zone. These observations demonstrate that the expression of ER alpha and ER beta displays different spatial-temporal patterns during human cortical and hippocampal development and suggest that both ERs may play distinct roles in several processes related to prenatal brain development.