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Estradiol and the Development of the Cerebral Cortex: An Unexpected Role? - PubMed

  • ️Mon Jan 01 2018

Review

Estradiol and the Development of the Cerebral Cortex: An Unexpected Role?

Matthew C S Denley et al. Front Neurosci. 2018.

Abstract

The cerebral cortex undergoes rapid folding in an "inside-outside" manner during embryonic development resulting in the establishment of six discrete cortical layers. This unique cytoarchitecture occurs via the coordinated processes of neurogenesis and cell migration. In addition, these processes are fine-tuned by a number of extracellular cues, which exert their effects by regulating intracellular signaling pathways. Interestingly, multiple brain regions have been shown to develop in a sexually dimorphic manner. In many cases, estrogens have been demonstrated to play an integral role in mediating these sexual dimorphisms in both males and females. Indeed, 17β-estradiol, the main biologically active estrogen, plays a critical organizational role during early brain development and has been shown to be pivotal in the sexually dimorphic development and regulation of the neural circuitry underlying sex-typical and socio-aggressive behaviors in males and females. However, whether and how estrogens, and 17β-estradiol in particular, regulate the development of the cerebral cortex is less well understood. In this review, we outline the evidence that estrogens are not only present but are engaged and regulate molecular machinery required for the fine-tuning of processes central to the cortex. We discuss how estrogens are thought to regulate the function of key molecular players and signaling pathways involved in corticogenesis, and where possible, highlight if these processes are sexually dimorphic. Collectively, we hope this review highlights the need to consider how estrogens may influence the development of brain regions directly involved in the sex-typical and socio-aggressive behaviors as well as development of sexually dimorphic regions such as the cerebral cortex.

Keywords: 17β-estradiol; aromatase; brain synthesized; cortical plate; migration; neurogenesis; sexual dimorphism; subventricular zone.

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Figures

Figure 1
Figure 1

Gross morphological schematic of sub-compartments in the developing rodent cortex. Representative image of developing cortex. Electroporation of eGFP was performed at E14.5 and brains collected at P0 as previously described (Srivastava et al., 2012a,b). The cortex is comprised of four morphologically distinct regions, the VZ, SVZ, IZ, and CP. Further to this there are the MAZ and MZ, located in the IZ and CP respectively. Located on the basal surface of the cortex proximal to the cerebral ventricles is the VZ responsible for generation of NSCs. Beyond the VZ, the SVZ contains proliferating and early differentiating neural progenitors. Between the SVZ and IZ, the MAZ is a point of accumulation of polarizing cells. After which the cells migrate through the IZ to the CP where terminal translocation takes place. This brief outline is the general schematic throughout development of the cortex. Cells migrate to the outmost layer and continually build on top of each other in a sedimentary manner. IZ, intermediate zone; MAZ, multipolar cell accumulation zone; CP, cortical plate; GFP, green fluorescence; NSCs, Neural Stem Cells; VZ, ventricular zone; SVZ, subventricular zone; MZ, marginal zone.

Figure 2
Figure 2

General schematic diagram of molecular events that regulate neurogenesis and proliferation in the VZ. Neuroblasts, or NSCs divide asymmetrically, their progeny inherits either high notch and mPar3 or low notch and mPar3. RGCs receive higher notch signaling, their counterpart receives lower notch signaling and becomes an IPC. E2 inhibits Hes1 expression, resulting in increased division by inhibition of neurogenins, Pax6, and BM88. ERß is able to modulate N and E-Cadherin levels, which stabilizes end-feet of radial scaffolds and mediates adhesion. Depending on the expression of Sox1 or Pax6 a progenitor will join the rapidly or slowly ascending pool. Sox1-expressing populations (Apical progenitors) are released rapidly but remaining in the deeper layers of the CP. Pax6-expressing populations (Basal progenitors) are released slowly and comprise the superficial neurons of the CP. E2 has also shown to increase proliferation of NSCs through stimulation of p21 and increasing EGF expression. miR-26 may increase E2 synthesis or ER expression to meet this end. E2 is also able to increase neuritogenesis, leading to the formation of an axon. It accomplishes this via GPER and ERα, which are able to stimulate neuritogenesis through Ngn3 and Neuroglobin/Akt, respectively. E2, Estradiol; VZ, ventricular zone; RGC, radial glial cell; NSCs, neural stem cells; IPC, intermediate progenitor cell; Ngn, neurogenin; GLAST, astrocyte-specific glutamate transporter; BLBP, brain-lipid binding protein; GFAP, glial fibrillary acidic protein; ERα, estrogen receptor alpha; ERß, estrogen receptor beta; GPER, G-protein estrogen receptor; EGF, epidermal growth factor; CP, cortical plate.

Figure 3
Figure 3

General schematic diagram of molecular events that regulate proliferation, differentiation and the initiation of migration in the SVZ. Progenitor populations in the SVZ and outer SVZ undergo proliferation, differentiation, polarization, which are controlled to achieve either neural population increases or migration. In both these populations, collections of cellular processes are regulated to shift balance between proliferation and differentiation. Cadherins cause cell-cell interactions through Wnt/Akt signaling, which result in altered levels of Pax6 or Sox1 expression. Cadherins increase expression of actin dynamic molecules and N-glycan. Resulting in axonal growth and migration, which involves incorporation of Tbr2, Nestin, and the SFK/Fyn/Cdk5 pathway. Cadherins influence the cell cycle through inhibition of the growth factor FGF and EphA4, which results in decreased proliferation and increased differentiation to allow migration. E2 is able to increase FGF/EphA4 action leading to greater proliferation. This action is achieved through E2 stimulating Pax6 through E-Cdk2. Polarization of migrating neurons in the SVZ can be accomplished by the coupling of Cdc42 to an aPKC/mPar6/mPar3 complex. SVZ, subventricular zone; miR, microRNA; E2, Estradiol; ERα, estrogen receptor alpha; ERß, estrogen receptor beta; GPER, G-protein estrogen receptor; aPKC, atypical protein kinase C; FGF, fibroblast growth factor; FRS2a, fibroblast growth factor receptor substrate 2a; G1, Gap 1 phase; SFK, Src family kinase; EphA4, Ephrin type-A receptor 4; Fyn, Src tyrosine-protein kinase fyn; NSCs, neural stem cells.

Figure 4
Figure 4

General schematic of corticogenesis in the IZ and MAZ, including differentiation and migration. The IZ facilitates cytoskeleton changes that affect the morphology of the migrating cell, much of this will occur in the MAZ. The MAZ is an accumulation ground for multipolar cells that are forming into mature bipolar neurons, which can then enter into the CP. The MAZ is comprised of two populations SEP and REP. Whereas the REP population passes straight through the MAZ, the SEP remains in the MAZ for much longer. Ultimately, the SEP forms the more superficial layer of the CP. REP can be distinguished from SEPs as they are Tbr2+. Crossing from the MAZ to IZ requires a transition from MP to BP, which is initiated by Ngn2, which inhibits RhoA and MAPK that have a downstream effect on Cofilin. Cofilin interacts with RGCs to increase cytoskeleton dynamics and affect a neuronal morphology. Cofilin can also be inhibited by RhoA, which is modulated through ERα. Oscillation between GDP and GTP control orientation and polarization of cells within the MAZ. This is achieved through lamellipodium formation and interaction with the cofilin system. Upregulation of Tiam1 or E2 can result in activation of Tiam1/Rac/Erk signaling, which stimulates BP cells to migrate through the IZ. Tiam1 also activates Rac1/NMDA to alter actin dynamics, which results in increased elongation, synaptogenesis and dendritogenesis. This process can be negatively regulated by ERβ or actively upregulated by Ngn3 through Cdk5/p35 activating a CRM1 shuttle. RGCs are stimulated to move toward the CP by interaction with BDNF. E2 stimulation via PI3K/Akt signaling can cause BDNF expression. BDNF binds to TrkB and upregulates Rac/Tiam1/P-Rex1 activity. Through Cux1 and E2 (ERβ), proliferation is inhibited at this stage allowing for migration to take place. Both Cux1 and E2 inhibit p27, which stops proliferating cells at the G1 phase. E2, estradiol; IZ, intermediate zone; MAZ multipolar cell accumulation zone; CP, cortical plate; RGC, Radial glial cell; ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; BP, bipolar; MP, multipolar; SEP, slow exiting population; REP, rapidly exiting population; BDNF, brain-derived neurotrophic factor; NMDA, N-methyl-D-aspartate; TrkB, Tropomyosin receptor kinase B; MAPK, mitogen-activated protein kinase; PI3K, Phosphoinositide 3 kinase; Akt, Protein Kinase B; bRG/bIP, basal radial glia/intermediate progenitor; aRG/aIP, apical radial glia/intermediate progenitor; G(D/T)P, guanosine (di/tri)-phosphate; CRM1, chromosomal maintenance 1/exportin 1; Cux1, cut like homeobox 1; RhoA, Ras homolog gene family, A; EphA4, Ephrin type-A receptor 4; Tiam1, T-cell lymphoma Invasion And Metastasis 1; Erk, extracellular signal-regulated kinases; Tbr2, T-box brain 2; E-Cdk2, G1 phase specific Cyclin E, Cyclin-dependent kinase 2; NSCs, neural stem cells.

Figure 5
Figure 5

General schematic of terminal translocation and differentiation in the CP during development. Within the CP SEP neurons (green) have high expression of Cux2 and low expression of β-catenin, whereas REP neurons (red) have high expression of β-catenin and low expression of Cux2. Satb1 positive cells express in the superficial layers of the MZ, which overlap with Tbr1 expression. Terminal translocation and therefore lamination rely on regulation by FoxG1 for the SEP neurons and radial distribution of Satb2 expressing REP neurons is regulated by Robo1. FoxG1 on deep-layer progenitors through transcription switches their progeny to upper-layer neurons through repression of Tbr1. After exiting the cell cycle, Satb2-expressing cells immediately migrate to the upper layers of the cortical plate. Satb2 expressing cells are much more reliant on the reelin/Dab1 and Ephrin-A pathways for cortical migration. Reelin binds to the RGCs by VLDLR and Apoer2 receptors (Lane-Donovan and Herz, 2017), which causes the adaptor protein Dab1 to become phosphorylated. Upon phosphorylation by SFKs, Dab1 recruits various downstream molecules including PI3K and Lis1. E2 is able to inhibit VLDLR/ApoER, modulates reelin's mechanisms in cortical migration. Reelin's interaction with cadherin is also essential for the termination of migration. Through regulating terminal translocation, the reelin/Dab1/Rap1/N-Cadherin signaling pathway leads to the inside-out lamination of the cortex. Nectin molecules expressed in the Cajal-Retzius cell (Nectin1) and the migrating neuron (Nectin3) are also necessary for somal translocation. The initiation of detachment is signaled by SC1, which is expressed on the surface at the top and bottom of RGCs surfaces. The anti-adhesive signal is crucial to proper cortical development, as the absence of SC1 results in failure of neurons to detach and properly position. Dab1 interacts with Cullin5 in the migrating cell to accumulate in the appropriate cortical layer. Termination of polarization upon reaching the appropriate location is met by the degradation of reelin receptors, N-cadherin and Dab1 by exocytosis and endocytosis. E2, Estradiol; IZ, intermediate zone; MAZ, multipolar cell accumulation zone; CP, cortical plate; RGC, Radial glial cell; ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; BP, bipolar; MP, multipolar; SEP, slow exiting population; REP, rapidly exiting population; SFK, Src family kinases; PI3K, Phosphoinositide 3 kinase; SC1, SPARC-like1; VLDLR, very low-density lipoprotein receptor; ApoER2, apolipoprotein E receptor 2; Cux2, cut like homeobox 2; FoxG1, Forkhead Box G1; Dab1, Disabled-1; Tbr1, T-box brain 1; Lis-1, Lissencephaly-1; Crk, (p38/adaptor molecule crk); C3G, CRK SH3-binding GNRP; Rap1, Ras-like GTPase; Satb(1/2) Special At-rich sequence binding protein (1/2); Robo1, Roundabout Guidance Receptor 1; EphA4, Ephrin type-A receptor 4; NSCs, neural stem cells.

Figure 6
Figure 6

An outline of the pathways influenced by estrogenic signaling to drive cortical development. Representative image of developing cortex. Electroporation of eGFP was performed at E14.5 and brains collected at P0 as previously described (Srivastava et al., 2012a,b). Representative image of a coronal rodent brain slice at P0 during cortical development. Estrogen (Estradiol/17ß-estradiol) is shown interacting in pathways outlined in Figures 1–4. that are involved in neurogenesis, proliferation, differentiation and migration. We propose that Estradiol may be able to affect the proliferative status of the progenitor pool through Pax6 and kinase inhibitors through ERß or ER. Through ERß, Estradiol can affect migration by marking terminal translocation points, therefore setting lamination boundaries. Estradiol is able to influence orientation through a number of mechanisms, which has been shown specifically in GFAP+ RGCs and mediated through ERß. Through ERß, Estradiol also alters the cytoskeleton dynamics to initiate migration. Cytoskeleton dynamics are also affected by GPER to increase neuritogenesis, which will later form axons and dendrites. Estradiol also alters differentiation state by increasing Wnt/ß-catenin signaling, which furthers dendritogenesis. Estradiol is able to negatively regulate migration and proliferation by increasing miR-9, which inhibits these processes. In regards to proliferation, it is hypothesized that ERα is primarily responsible for mediating the action of estrogenic signaling. Estradiol also interacts with reelin signaling in the CP and MZ, both directly by increasing expression and indirectly by stimulation of ApoE gene expression, which increases the activity of ApoER to affect the morphology of the cortex and cytoarchitecture of the CP. E2, estradiol; IZ, intermediate zone; MAZ, multipolar cell accumulation zone; CP, cortical plate; ERß, estrogen receptor beta; ERα, estrogen receptor alpha; GPER, G-protein estrogen receptor; miR-x, microRNA; ApoER2, apolipoprotein E receptor 2; Wnt, Wingless-type; BDNF, brain-derived neurotropic factor; p21, cyclin-dependent kinase inhibitor 1A/Cip1; p27, cyclin-dependent kinase inhibitor 1B/Kip1; Ngn, neurogenin; Cdc25A, Cell division cycle 25 homolog A; VZ, ventricular zone; SVZ, subventricular zone.

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