Temporal Patterns of Emergence and Spatial Distribution of Sulcal Pits During Fetal Life

Abstract Sulcal pits are thought to represent the first cortical folds of primary sulci during neurodevelopment. The uniform spatial distribution of sulcal pits across individuals is hypothesized to be predetermined by a human-specific protomap which is related to functional localization under genetic controls in early fetal life. Thus, it is important to characterize temporal and spatial patterns of sulcal pits in the fetal brain that would provide additional information of functional development of the human brain and crucial insights into abnormal cortical maturation. In this paper, we investigated temporal patterns of emergence and spatial distribution of sulcal pits using 48 typically developing fetal brains in the second half of gestation. We found that the position and spatial variance of sulcal pits in the fetal brain are similar to those in the adult brain, and they are also temporally uniform against dynamic brain growth during fetal life. Furthermore, timing of pit emergence shows a regionally diverse pattern that may be associated with the subdivisions of the protomap. Our findings suggest that sulcal pits in the fetal brain are useful anatomical landmarks containing detailed information of functional localization in early cortical development and maintaining their spatial distribution throughout the human lifetime.

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Allopregnanolone in the brain and blood after disruption of the hypothalamic-pituitary-adrenal axis in fetal sheep

Journal of Endocrinology ◽

10.1677/joe.0.1820081 ◽

2004 ◽

Vol 182 (1) ◽

pp. 81-88 ◽

Cited By ~ 11

Author(s):

PN Nguyen ◽

I Ross Young ◽

DW Walker ◽

JJ Hirst

Keyword(s):

Adrenal Gland ◽

De Novo ◽

Fetal Brain ◽

Adult Brain ◽

Neuroactive Steroid ◽

Control Mechanisms ◽

Fetal Life ◽

Fetal Sheep ◽

Adrenal Steroid ◽

The Brain

Neuroactive steroids may be synthesised in the brain either de novo from cholesterol or from blood-borne precursors. Concentrations of a GABAA receptor agonist, allopregnanolone, in the fetal brain exceed those in the circulation, and are markedly higher than adult brain concentrations. We used fetal hypophysectomy or adrenalectomy to elucidate the contribution of hypothalamic-pituitary factors and adrenal steroid secretion to the overall neuroactive steroid level in both the fetal brain and the fetal circulation. Hypophysectomy or adrenalectomy was performed between 108 and 112 days of gestation (term approximately 147 days) and fetal tissues were collected at 140 days of gestation. Immunoreactive (ir) ACTH and cortisol in the plasma were significantly reduced after hypophysectomy, whereas adrenalectomy led to increased irACTH but significantly decreased cortisol concentrations, as expected. Brain concentrations of allopregnanolone, progesterone and pregnenolone did not change significantly in fetuses that underwent either hypophysectomy or adrenalectomy; however, concentrations in the plasma and content in the adrenal gland were decreased. Expression of cytochrome P450 scc and 5alpha-reductase type II (5alphaRII) in the brain, measured by western immunoblotting, did not change after either hypophysectomy or adrenalectomy but, after hypophysectomy, expression of P450 scc in the adrenal gland was significantly decreased and that of 5alphaRII remained unchanged. These findings suggest that the regulation of the neuroactive steroid content in the fetal brain is independent of adrenal steroidogenesis and hypothalamic-pituitary factors. Furthermore, the absence of a change in enzyme expression in the brain suggests that the control of the expression of these enzymes is independent of hypothalamic-pituitary factors. Thus local control mechanisms within the brain may be responsible for maintaining the high neurosteroid content present during fetal life, as these mechanisms are independent of adrenal steroid production.

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Transfer of rhodamine-123 into the brain and cerebrospinal fluid of fetal, neonatal and adult rats

Fluids and Barriers of the CNS ◽

10.1186/s12987-021-00241-8 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Liam M. Koehn ◽

Katarzyna M. Dziegielewska ◽

Mark D. Habgood ◽

Yifan Huang ◽

Norman R. Saunders

Keyword(s):

Cerebrospinal Fluid ◽

Fetal Brain ◽

Maternal Blood ◽

Adult Brain ◽

Rhodamine 123 ◽

Patient Specific ◽

Adult Rats ◽

Blood Brain ◽

The Brain ◽

Brain Barriers

Abstract Background Adenosine triphosphate binding cassette transporters such as P-glycoprotein (PGP) play an important role in drug pharmacokinetics by actively effluxing their substrates at barrier interfaces, including the blood-brain, blood-cerebrospinal fluid (CSF) and placental barriers. For a molecule to access the brain during fetal stages it must bypass efflux transporters at both the placental barrier and brain barriers themselves. Following birth, placental protection is no longer present and brain barriers remain the major line of defense. Understanding developmental differences that exist in the transfer of PGP substrates into the brain is important for ensuring that medication regimes are safe and appropriate for all patients. Methods In the present study PGP substrate rhodamine-123 (R123) was injected intraperitoneally into E19 dams, postnatal (P4, P14) and adult rats. Naturally fluorescent properties of R123 were utilized to measure its concentration in blood-plasma, CSF and brain by spectrofluorimetry (Clariostar). Statistical differences in R123 transfer (concentration ratios between tissue and plasma ratios) were determined using Kruskal-Wallis tests with Dunn’s corrections. Results Following maternal injection the transfer of R123 across the E19 placenta from maternal blood to fetal blood was around 20 %. Of the R123 that reached fetal circulation 43 % transferred into brain and 38 % into CSF. The transfer of R123 from blood to brain and CSF was lower in postnatal pups and decreased with age (brain: 43 % at P4, 22 % at P14 and 9 % in adults; CSF: 8 % at P4, 8 % at P14 and 1 % in adults). Transfer from maternal blood across placental and brain barriers into fetal brain was approximately 9 %, similar to the transfer across adult blood-brain barriers (also 9 %). Following birth when placental protection was no longer present, transfer of R123 from blood into the newborn brain was significantly higher than into adult brain (3 fold, p < 0.05). Conclusions Administration of a PGP substrate to infant rats resulted in a higher transfer into the brain than equivalent doses at later stages of life or equivalent maternal doses during gestation. Toxicological testing of PGP substrate drugs should consider the possibility of these patient specific differences in safety analysis.

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Insulin and insulinlike growth factor 1 (IGF-1) receptors during central nervous system development: expression of two immunologically distinct IGF-1 receptor beta subunits.

Molecular and Cellular Biology ◽

10.1128/mcb.9.7.2806 ◽

1989 ◽

Vol 9 (7) ◽

pp. 2806-2817 ◽

Cited By ~ 52

Author(s):

R S Garofalo ◽

O M Rosen

Keyword(s):

Growth Factor ◽

Tyrosine Kinase ◽

System Development ◽

Fetal Brain ◽

Nervous System Development ◽

Adult Brain ◽

Beta Subunit ◽

Tyrosine Kinase Domain ◽

Beta Subunits ◽

Insulinlike Growth Factor

Insulin and insulinlike growth factor 1 (IGF-1) receptors are present in brain, yet their function remains obscure. Expression of these tyrosine kinase-bearing growth factor receptors during rat brain development was examined by using three antipeptide antibodies directed against epitopes in the beta subunits (AbP2, AbP4, and AbP5). All three antibodies recognized both insulin and IGF-1 receptors. Membranes were prepared from fetal brains (14 to 21 days of gestation), neonatal brain (postnatal day 1), and adult brain. Immunoblot analyses using AbP4 and AbP5 revealed a 92-kilodalton (kDa) protein that corresponded to the beta subunit of the insulin and IGF-1 receptors. Densitometric scanning of immunoblots indicated that receptor proteins were 4- to 10-fold more abundant in fetal brain membranes than in membranes from adult brain. Expression was highest during 16 to 18 days of gestation and declined thereafter to the relatively low level found in adult brain. Immunoblot analyses with AbP2 as well as ligand-activated receptor autophosphorylation revealed an additional protein of 97 kDa. This protein was phosphorylated in response to IGF-1 and was not directly recognized by AbP4 or AbP5. The covalent association of the 97-kDa protein with the 92-kDa beta subunit was indicated by the ability of AbP4 and AbP5 to immunoprecipitate both proteins under nonreducing conditions but only the 92-kDa protein after reduction. In contrast, AbP2 immunoprecipitated both proteins regardless of their association. This immunospecificity remained unchanged after deglycosylation of the isolated proteins. Two-dimensional tryptic phosphopeptide analysis showed that the 92- and 97-kDa subunits of the IGF-1 receptor are related but distinct proteins. Taken together, the data suggest that the 92- and 97-kDa subunits differ in primary amino acid sequence. Thus, two distinct beta subunits may be present in a single IGF-1 receptor in brain. These subunits have in common an epitope recognized by an antibody to the tyrosine kinase domain (AbP2) but differ in regions thought to be important in receptor kinase regulation and signal transduction.

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Importance of Adult Dmbx1 in Long-Lasting Orexigenic Effect of Agouti-Related Peptide

Endocrinology ◽

10.1210/en.2015-1560 ◽

2016 ◽

Vol 157 (1) ◽

pp. 245-257 ◽

Cited By ~ 1

Author(s):

Seiichiro Hirono ◽

Eun Young Lee ◽

Shunsuke Kuribayashi ◽

Takahiro Fukuda ◽

Naokatsu Saeki ◽

...

Keyword(s):

Mouse Strain ◽

Energy Homeostasis ◽

Expression Patterns ◽

Critical Role ◽

Fetal Brain ◽

Cre Recombinase ◽

Calcitonin Gene Related Peptide ◽

Adult Brain ◽

Related Peptide ◽

Calcitonin Gene

Abstract Dmbx1 is a brain-specific homeodomain transcription factor expressed primarily during embryogenesis, and its systemic disruption (Dmbx1−/−) in the ICR mouse strain resulted in leanness associated with impaired long-lasting orexigenic effect of agouti-related peptide (AgRP). Because spatial and temporal expression patterns of Dmbx1 change dramatically during embryogenesis, it remains unknown when and where Dmbx1 plays a critical role in energy homeostasis. In the present study, the physiological roles of Dmbx1 were examined by its conditional disruption (Dmbx1loxP/loxP) in the C57BL/6 mouse strain. Although Dmbx1 disruption in fetal brain resulted in neonatal lethality, its disruption by synapsin promoter-driven Cre recombinase, which eliminated Dmbx1 expression postnatally, exempted the mice (Syn-Cre;Dmbx1loxP/loxP mice) from lethality. Syn-Cre;Dmbx1loxP/loxP mice show mild leanness and impaired long-lasting orexigenic action of AgRP, demonstrating the physiological relevance of Dmbx1 in the adult. Visualization of Dmbx1-expressing neurons in adult brain using the mice harboring tamoxifen-inducible Cre recombinase in the Dmbx1 locus (Dmbx1CreERT2/+ mice) revealed Dmbx1 expression in small numbers of neurons in restricted regions, including the lateral parabrachial nucleus (LPB). Notably, c-Fos expression in LPB was increased at 48 hours after AgRP administration in Dmbx1loxP/loxP mice but not in Syn-Cre;Dmbx1loxP/loxP mice. These c-Fos-positive neurons in LPB did not coincide with neurons expressing Dmbx1 or melanocortin 4 receptor but did coincide with those expressing calcitonin gene-related peptide. Accordingly, Dmbx1 in the adult LPB is required for the long-lasting orexigenic effect of AgRP via the neural circuitry involving calcitonin gene-related peptide neurons.

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Regulation of N-myc gene expression: use of an adenovirus vector to demonstrate posttranscriptional control

Molecular and Cellular Biology ◽

10.1128/mcb.10.12.6700-6708.1990 ◽

1990 ◽

Vol 10 (12) ◽

pp. 6700-6708

Author(s):

L E Babiss ◽

J M Friedman

Keyword(s):

Recombinant Adenovirus ◽

Wilms Tumor ◽

Fetal Brain ◽

Adenovirus Vector ◽

Cell Types ◽

Adult Brain ◽

Posttranscriptional Control ◽

Equivalent Rate ◽

Myc Gene ◽

Recombinant Adenovirus Vector

We present evidence that differences in the levels of N-myc mRNA among different cell types are the result of posttranscriptional control. First, we noted that while steady-state mouse N-myc mRNA could be detected only in fetal mouse brain, it was transcribed at an equivalent rate in adult brain, liver, spleen, and placenta and in fetal brain. Similarly, the human N-myc gene was transcribed at an equivalent rate in HeLa cells, which do not accumulate this RNA in the cytoplasm, and cell lines G401 (a Wilms tumor-derived cell line) and SKNMc (established from a primitive neuroepithelioma), which do express N-myc RNA. As expected, the N-myc promoter functioned at equivalent rates, as demonstrated by the level of a reporter gene, when introduced into these cell types by using a recombinant adenovirus vector. The suggestion that posttranscriptional mechanisms control the level of this RNA was supported by the observation that sequences in the N-myc third exon specifically decreased the level of E1A mRNA when these sequences were placed downstream of the E1A promoter in a recombinant adenovirus. Finally, we further localized these sequences to a 600-bp fragment of the third exon by introducing various subclones of this sequence downstream of the E1A promoter in both viral and plasmid vectors.

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The Expression and Distributions of ANP32A in the Developing Brain

BioMed Research International ◽

10.1155/2015/207347 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Shanshan Wang ◽

Yunliang Wang ◽

Qingshan Lu ◽

Xinshan Liu ◽

Fuyu Wang ◽

...

Keyword(s):

Cerebral Cortex ◽

Fetal Brain ◽

Tissue Expression ◽

Developing Brain ◽

Adult Brain ◽

Mammalian Brain ◽

Dependent Manner ◽

Growing Up ◽

Embryonic Mouse ◽

And Function

Acidic (leucine-rich) nuclear phosphoprotein 32 family, member A (ANP32A), has multiple functions involved in neuritogenesis, transcriptional regulation, and apoptosis. However, whether ANP32A has an effect on the mammalian developing brain is still in question. In this study, it was shown that brain was the organ that expressed the most abundant ANP32A by human multiple tissue expression (MTE) array. The distribution of ANP32A in the different adult brain areas was diverse dramatically, with high expression in cerebellum, temporal lobe, and cerebral cortex and with low expression in pons, medulla oblongata, and spinal cord. The expression of ANP32A was higher in the adult brain than in the fetal brain of not only humans but also mice in a time-dependent manner. ANP32A signals were dispersed accordantly in embryonic mouse brain. However, ANP32A was abundant in the granular layer of the cerebellum and the cerebral cortex when the mice were growing up, as well as in the Purkinje cells of the cerebellum. The variation of expression levels and distribution of ANP32A in the developing brain would imply that ANP32A may play an important role in mammalian brain development, especially in the differentiation and function of neurons in the cerebellum and the cerebral cortex.

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Characterization of human fetal brain endothelial cells reveals barrier properties suitable for in vitro modeling of the BBB with syngenic co-cultures

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17708690 ◽

2017 ◽

Vol 38 (5) ◽

pp. 888-903 ◽

Cited By ~ 10

Author(s):

Allison M Andrews ◽

Evan M Lutton ◽

Lee A Cannella ◽

Nancy Reichenbach ◽

Roshanak Razmpour ◽

...

Keyword(s):

Endothelial Cells ◽

Neurovascular Unit ◽

Fetal Brain ◽

Barrier Properties ◽

Endothelial Activation ◽

Fetal Tissue ◽

In Vitro Models ◽

Adult Brain ◽

Alternative Source

Endothelial cells (ECs) form the basis of the blood–brain barrier (BBB), a physical barrier that selectively restricts transport into the brain. In vitro models can provide significant insight into BBB physiology, mechanisms of human disease pathology, toxicology, and drug delivery. Given the limited availability of primary human adult brain microvascular ECs ( aBMVECs), human fetal tissue offers a plausible alternative source for multiple donors and the opportunity to build syngenic tri-cultures from the same host. Previous efforts to culture fetal brain microvascular ECs ( fBMVECs) have not been successful in establishing mature barrier properties. Using optimal gestational age for isolation and flow cytometry cell sorting, we show for the first time that fBMVECs demonstrate mature barrier properties. fBMVECs exhibited similar functional phenotypes when compared to aBMVECs for barrier integrity, endothelial activation, and gene/protein expression of tight junction proteins and transporters. Importantly, we show that tissue used to culture fBMVECs can also be used to generate a syngenic co-culture, creating a microfluidic BBB on a chip. The findings presented provide a means to overcome previous challenges that limited successful barrier formation by fBMVECs. Furthermore, the source is advantageous for autologous reconstitution of the neurovascular unit for next generation in vitro BBB modeling.

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Three differentially expressed Na,K-ATPase alpha subunit isoforms: structural and functional implications.

The Journal of Cell Biology ◽

10.1083/jcb.105.4.1855 ◽

1987 ◽

Vol 105 (4) ◽

pp. 1855-1865 ◽

Cited By ~ 163

Author(s):

V L Herrera ◽

J R Emanuel ◽

N Ruiz-Opazo ◽

R Levenson ◽

B Nadal-Ginard

Keyword(s):

Fetal Brain ◽

Amino Acid Sequences ◽

Adult Brain ◽

Alpha Subunit ◽

Rat Tissues ◽

S1 Nuclease ◽

Biochemical Basis ◽

Alpha Subunits ◽

Subunit Isoforms ◽

Nuclease Mapping

We have characterized cDNAs coding for three Na,K-ATPase alpha subunit isoforms from the rat, a species resistant to ouabain. Northern blot and S1-nuclease mapping analyses revealed that these alpha subunit mRNAs are expressed in a tissue-specific and developmentally regulated fashion. The mRNA for the alpha 1 isoform, approximately equal to 4.5 kb long, is expressed in all fetal and adult rat tissues examined. The alpha 2 mRNA, also approximately equal to 4.5 kb long, is expressed predominantly in brain and fetal heart. The alpha 3 cDNA detected two mRNA species: a approximately equal to 4.5 kb mRNA present in most tissues and a approximately equal to 6 kb mRNA, found only in fetal brain, adult brain, heart, and skeletal muscle. The deduced amino acid sequences of these isoforms are highly conserved. However, significant differences in codon usage and patterns of genomic DNA hybridization indicate that the alpha subunits are encoded by a multigene family. Structural analysis of the alpha subunits from rat and other species predicts a polytopic protein with seven membrane-spanning regions. Isoform diversity of the alpha subunit may provide a biochemical basis for Na,K-ATPase functional diversity.

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A novel human gene whose product shares homology with bovine brain-specific protein p25 is expressed in fetal brain but not in adult brain

Journal of Human Genetics ◽

10.1007/s100380200037 ◽

2002 ◽

Vol 47 (5) ◽

pp. 266-268 ◽

Cited By ~ 13

Author(s):

Z. Zhang ◽

C. Wu ◽

W. Huang ◽

S. Wang ◽

E. Zhao ◽

...

Keyword(s):

Human Gene ◽

Fetal Brain ◽

Specific Protein ◽

Bovine Brain ◽

Adult Brain

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Recent Developments in Understanding Barrier Mechanisms in the Developing Brain: Drugs and Drug Transporters in Pregnancy, Susceptibility or Protection in the Fetal Brain?

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev-pharmtox-010818-021430 ◽

2019 ◽

Vol 59 (1) ◽

pp. 487-505 ◽

Cited By ~ 9

Author(s):

Norman R. Saunders ◽

Katarzyna M. Dziegielewska ◽

Kjeld Møllgård ◽

Mark D. Habgood

Keyword(s):

Fetal Brain ◽

Adult Brain ◽

Brain Barrier ◽

Normal Brain ◽

Developmentally Regulated ◽

Protective Mechanisms ◽

Control Drug ◽

Newborn Brain ◽

Recent Developments ◽

In Pregnancy

Efflux mechanisms situated in various brain barrier interfaces control drug entry into the adult brain; this review considers the effectiveness of these protective mechanisms in the embryo, fetus, and newborn brain. The longstanding belief that the blood-brain barrier is absent or immature in the fetus and newborn has led to many misleading statements with potential clinical implications. The immature brain is undoubtedly more vulnerable to damage by drugs and toxins; as is reviewed here, some developmentally regulated normal brain barrier mechanisms probably contribute to this vulnerability. We propose that the functional status of brain barrier efflux mechanisms should be investigated at different stages of brain development to provide a rational basis for the use of drugs in pregnancy and in newborns, especially in those prematurely born, where protection usually provided by the placenta is no longer present.

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