Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 May 14:5:3.
doi: 10.3389/fnmol.2012.00064. eCollection 2012.

The calcium: an early signal that initiates the formation of the nervous system during embryogenesis

Affiliations

The calcium: an early signal that initiates the formation of the nervous system during embryogenesis

Catherine Leclerc et al. Front Mol Neurosci. .

Abstract

The calcium (Ca(2+)) signaling pathways have crucial roles in development from fertilization through differentiation to organogenesis. In the nervous system, Ca(2+) signals are important regulators for various neuronal functions, including formation and maturation of neuronal circuits and long-term memory. However, Ca(2+) signals are also involved in the earliest steps of neurogenesis including neural induction, differentiation of neural progenitors into neurons, and the neuro-glial switch. This review examines when and how Ca(2+) signals are generated during each of these steps with examples taken from in vivo studies in vertebrate embryos and from in vitro assays using embryonic and neural stem cells (NSCs). During the early phases of neurogenesis few investigations have been performed to study the downstream targets of Ca(2+) which posses EF-hand in their structure. This opens an entire field of research. We also discuss the highly specific nature of the Ca(2+) signaling pathway and its interaction with the other signaling pathways involved in early neural development.

Keywords: EF-hand; calcium signaling; early neural development; neural induction; neural progenitor; neuro-glial switch; stem cell.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Schematic representations of the early phases of neural development in the embryo (A) and in Esc (B). (A) Neural induction which converts ectoderm into neuroectoderm is regulated by the coordinated actions of BMP, Wnt, and FGF signaling pathways. Neuroectodermal cells are undifferentiated dividing neuroepithelial cells that will latter differentiate into neurons (neurogenesis period) and in a second phase into glial cells (gliogenesis period). Among the factors that control the selection of neuronal progenitors from the neuroectodermal cells and their commitment to differentiate along the neuronal lineage are the proneural bHLH genes. In vertebrates, proneural bHLH genes are first expressed in the neuroectodermal cells, already committed to the neural fate. The neuronal progenitors have a limited mitotic potential. Differentiation occurs in a defined temporal sequence, neurons being generated first, followed by glial cells. The switch from neurogenesis to gliogenesis is controlled by both extrinsic and intrinsic signals and is the result of changes in the progenitor properties within the same pool of neuronal progenitors. (B) In ESC neural induction and specification of ES-derived neural progenitors follow the same cues as in the embryo to give rise to populations of neurons and glial cells. Black curved arrows indicate self-renewing cells. Abbreviations: BMP, bone morphogenetic protein; bHLH genes, basic helix-loop-helix genes; ESC, embryonic stem cell; NSC, neural stem cell.
Figure 2
Figure 2
Schematic representation of the signaling pathways occurring during neural induction in the amphibian ectoderm cells (left panel) and in the ESCs (right panel). In both systems, neural commitment of naïve cells requires the activation of FGF/ERK signaling and the inhibition of BMP signaling by noggin and via the Erk-dependent phosphorylation of Smad1 at linker domain. An increase in intracellular Ca2+ concentration is also a common signal that drives embryonic cells toward the neural fate. However, the control of Ca2+ homeostasis differs between amphibian ectodermal cells and ESCs. While in amphibian, the main source of Ca2+ increase appears to rely on an influx through VOCCs (likely DHP-Ca2+ channels), ESCs do not express VOCC. In ESCs, the regulation of intracellular Ca2+ level depends on the activity of the SERCA2 pump, negatively regulated by neuronatin. Both cell types expressed TRP channels, probably TRPC, which could contribute to the Ca2+ signals. Gating of the VOCC in ectodermal cells could be due to membrane depolarization induced by the activation of TRPC. In ESCs, a direct link between intracellular Ca2+ increase and Erk phosphorylation has been established; in ectodermal cells the question of the amplification of the initial Ca2+ influx by the release of Ca2+ from the ER remains open. However, in both models Ca2+ signals participate in the inhibition of the BMP signaling pathway, either directly or indirectly via Erk-dependent phosphorylation of Smad1. Abbreviations: BMP, bone morphogenetic protein; BMPR, BMP receptor; ER, endoplasmic reticulum; ESC, embryonic stem cell; FGFR, fibroblast growth factor receptor; Nnat, neuronatin; Neural SC, neural stem cell; SERCA2, sarco/endoplasmic reticulum Ca2+-ATPase, isoform2; TRPC, class C transient potential receptor; VOCC, voltage-operated Ca2+ channels.
Figure 3
Figure 3
Schematic diagrams of the temporal development of neural progenitors in the early stages of CNS formation. (A) Early neuroepithelial progenitors of the ventricular zone are columnar cells self-renewing by symmetric divisions. These cells can generate some neurons. (B) As neurogenesis proceeds, neuroepithelial cells are transformed into radial glial cells which ultimately will give rise to neurons and glial cells. Radial glia cells can undergo either symmetric divisions, generating two progenitors or asymmetric divisions, producing a neural progenitor and a neuron. Also illustrated is the interkinetic nuclear migration of the nuclei during the cell cycle in the VZ. The nucleus of a single neuroepithelial cell moves during the G1 phase, from the ventricular surface to the border of the VZ where it enters S phase. During G2, the nucleus moves down to the ventricular surface where it enter mitosis (M phase). Interkinetic nuclear migration in radial glial cells is confined to the VZ portion, does not extend to the border of the MZ. (C) In the cerebral cortex a second proliferative zone, the subventricular zone (SVZ), appears adjacent to the VZ; the postmitotic neurons and glia arise from both the ventricular and the subventricular zones. In the SVZ interkinetic nuclear migration does not occur, mitotic cells are found throughout the SVZ. Abbreviations: CNS, central nervous system; IZ, intermediate zone; MZ, marginal zone; SVZ, subventricular zone; VZ, ventricular zone.

Similar articles

Cited by

References

    1. Annaert W. G., Levesque L., Craessaerts K., Dierinck I., Snellings G., Westaway D., George-Hyslop P. S., Cordell B., Fraser P., De Strooper B. (1999). Presenilin 1 controls gamma-secretase processing of amyloid precursor protein in pre-golgi compartments of hippocampal neurons. J. Cell Biol. 147, 277–294 10.1083/jcb.147.2.277 - DOI - PMC - PubMed
    1. Arcuri F., Papa S., Meini A., Carducci A., Romagnoli R., Bianchi L., Riparbelli M. G., Sanchez J. C., Palmi M., Tosi P., Cintorino M. (2005). The translationally controlled tumor protein is a novel calcium binding protein of the human placenta and regulates calcium handling in trophoblast cells. Biol. Reprod. 73, 745–751 10.1095/biolreprod.105.042077 - DOI - PubMed
    1. Aruga J. (2004). The role of Zic genes in neural development. Mol. Cell. Neurosci. 26, 205–221 10.1016/j.mcn.2004.01.004 - DOI - PubMed
    1. Aruga J., Mikoshiba K. (2011). Role of BMP, FGF, calcium signaling, and zic proteins in vertebrate neuroectodermal differentiation. Neurochem. Res. 36, 1286–1292 10.1007/s11064-011-0422-5 - DOI - PMC - PubMed
    1. Bandyopadhyay S., Tfelt-Hansen J., Chattopadhyay N. (2010). Diverse roles of extracellular calcium-sensing receptor in the central nervous system. J. Neurosci. Res. 88, 2073–2082 10.1002/jnr.22391 - DOI - PubMed