Endocannabinoids (eCBs) have recently been identified as axon guidance cues shaping the connectivity of local GABAergic interneurons in the developing cerebrum. However, eCB functions during pyramidal cell specification and establishment of longrange axonal connections are unknown. Here, we show that eCB signaling is operational in subcortical proliferative zones from embryonic day 12 in the mouse telencephalon and controls the proliferation of pyramidal cell progenitors and radial migration of immature pyramidal cells. When layer patterning is accomplished, developing pyramidal cells rely on eCB signaling to initiate the elongation and fasciculation of their long-range axons. Accordingly, CB 1 cannabinoid receptor (CB1R) null and pyramidal cellspecific conditional mutant (CB 1R f/f,NEX-Cre ) mice develop deficits in neuronal progenitor proliferation and axon fasciculation. Likewise, axonal pathfinding becomes impaired after in utero pharmacological blockade of CB 1Rs. Overall, eCBs are fundamental developmental cues controlling pyramidal cell development during corticogenesis.excitation ͉ glutamate ͉ layer patterning ͉ neocortex ͉ neurogenesis P yramidal cell specification follows a sequential scenario in the developing cerebrum: commitment of progenitor cells to the neuronal lineage occurs in the subcortical proliferative ventricular zone (VZ) and subventricular zone (SVZ). Immature pyramidal cells undergo radial migration to populate the cortical plate (CP) (1), where they acquire layer-specific neurochemical and morphological diversity (2). Pyramidal cell positioning and patterning of their corticofugal and intracortical axons is in part achieved via transcriptional control acting throughout cellular identification (2). However, epigenetic microenvironmental cues, provided by neural progenitors, radial glia, and immature neurons, are also fundamental in attaining cortical cell identity with particularly robust effects on pathfinding and directional growth of long-range axons (3).Endocannabinoids [eCBs; anandamide (AEA) and 2-arachidonoylglycerol] control various forms of synaptic plasticity at cortical glutamatergic synapses in the postnatal brain (4) through functional CB 1 cannabinoid receptors (CB 1 Rs) (5). During brain development, eCBs control neuronal fate decision (6), interneuron migration (7), and axonal specification (8). Developmental eCB actions are underpinned by a temporally defined assembly of functional eCB signaling networks with coincident expression of sn-1-diacylglycerol lipases (DAGL␣/) (9) and N-arachidonoyl-phosphatidyl ethanolamine (NAPE)-selective phospholipase D involved in eCB synthesis, fatty-acid amide hydrolase (FAAH) (an enzyme preferentially degrading AEA), and CB 1 Rs (8). The selective axonal targeting of CB 1 Rs and DAGLs in immature neurons suggests that eCBs may function in either cell-autonomous (6, 9) or target-derived (8) manner to control axonal elongation and postsynaptic target selection, respectively.Although recent findings in both mammals (8) and nonmammalian v...
Endocannabinoids, particularly 2-arachidonoyl glycerol (2-AG), impact the directional turning and motility of a developing axon by activating CB 1 cannabinoid receptors (CB 1 Rs) in its growth cone. Recent findings posit that sn-1-diacylglycerol lipases (DAGL␣/) synthesize 2-AG in the motile axon segment of developing pyramidal cells. Coincident axonal targeting of CB 1 Rs and DAGLs prompts the hypothesis that autocrine 2-AG signaling facilitates axonal outgrowth. However, DAGLs alone are insufficient to account for the spatial specificity and dynamics of 2-AG signaling. Therefore, we hypothesized that local 2-AG degradation by monoacylglycerol lipase (MGL) must play a role. We determined how subcellular recruitment of MGL is temporally and spatially restricted to establish the signaling competence of 2-AG during axonal growth. MGL is expressed in central and peripheral axons of the fetal nervous system by embryonic day 12.5. MGL coexists with DAGL␣ and CB 1 Rs in corticofugal axons of pyramidal cells. Here, MGL and DAGL␣ undergo differential axonal targeting with MGL being excluded from the motile neurite tip. Thus, spatially confined MGL activity generates a 2-AG-sensing microdomain and configures 2-AG signaling to promote axonal growth. Once synaptogenesis commences, MGL disperses in stationary growth cones. The axonal polarity of MGL is maintained by differential proteasomal degradation because inhibiting the ubiquitin proteasome system also induces axonal MGL redistribution. Because MGL inactivation drives a CB 1 R-dependent axonal growth response, we conclude that 2-AG may act as a focal protrusive signal for developing neurons and whose regulated metabolism is critical for attaining correct axonal complexity.
Please cite this article as: Harkany, T., Keimpema, E., Barabás, K., Mulder, J., Endocannabinoid functions controlling neuronal specification during brain development, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 16A c c e p t e d M a n u s c r i p t AbstractEndocannabinoids (eCBs) regulate a broad range of physiological functions in the postnatal brain and are implicated in the neuropathogenesis of psychiatric and metabolic diseases. Accumulating evidence indicates that eCB signaling also serves key functions during neurodevelopment; and is inherently involved in the control of neurogenesis, neural progenitor proliferation, lineage segregation, and the migration and phenotypic specification of immature neurons. Recent advances in developmental biology define fundamental eCB-driven cellular mechanisms that also contribute to our understanding of the molecular substrates of prenatal drug, in particular cannabis, actions. Here, we summarize known organizing principles of eCB signaling systems in the developing telencephalon, and outline the sequence of decision points and underlying signaling pathways upon CB1 cannabinoid receptor activation that contribute to neuronal diversification in the developing brain. Finally, we discuss how these novel principles affect the formation of complex neuronal networks.Running title: Endocannabinoids in the developing brain.
In addition to classical genomic mechanisms, estrogen also exerts nonclassical effects via a signal transduction system on neurons. To study whether estrogen has a nonclassical effect on basal forebrain cholinergic system, we measured the intensity of cAMP response element-binding protein (CREB) phosphorylation (pCREB) in cholinergic neurons after administration of 17-estradiol to ovariectomized (OVX) mice. A significant time-dependent increase in the number of pCREB-positive cholinergic cells was detected after estrogen administration in the medial septum-diagonal band (MS-DB) and the substantia innominata (SI). The increase was first observed 15 min after estrogen administration. The role of classical estrogen receptors (ERs) was evaluated using ER knock-out mice in vivo. The estrogeninduced CREB phosphorylation in cholinergic neurons was present in ER knock-out mice but completely absent in ER␣ knock-out mice in MS-DB and SI. A series of in vitro studies demonstrated that estrogen acted directly on cholinergic neurons. Selective blockade of the mitogen activated protein kinase (MAPK) pathway in vivo completely prevented estrogen-induced CREB phosphorylation in cholinergic neurons in MS-DB and SI. In contrast, blockade of protein kinase A (PKA) was effective only in SI. Finally, studies in intact female mice revealed levels of CREB phosphorylation within cholinergic neurons that were similar to those of estrogen-treated OVX mice. These observations demonstrate an ER␣-mediated nonclassical effect of estrogen on the cholinergic neurons and that these actions are present under physiological conditions. They also reveal the role of MAPK and PKA-MAPK pathway activation in nonclassical estrogen signaling in the basal forebrain cholinergic neurons in vivo.
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