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Hes1: the maestro in neurogenesis

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Abstract

The process of neurogenesis is well orchestrated by the harmony of multiple cues in a spatiotemporal manner. In this review, we focus on how a dynamic gene, Hes1, is involved in neurogenesis with the view of its regulation and functional implications. Initially, we have reviewed the immense functional significance drawn by this maestro during neural development in a context-dependent manner. How this indispensable role of Hes1 in conferring the competency for neural differentiation partly relies on the direct/indirect mode of repression mediated by very specific structural and functional arms of this protein has also been outlined here. We also review the detailed molecular mechanisms behind the well-tuned oscillatory versus sustained expression of this antineurogenic bHLH repressor, which indeed makes it a master gene to implement the elusive task of neural progenitor propensity. Apart from the functional aspects of Hes1, we also discuss the molecular insights into the endogenous regulatory machinery that regulates its expression. Though Hes1 is a classical target of the Notch signaling pathway, we discuss here its differential expression at the molecular, cellular, and/or regional level. Moreover, we describe how its expression is fine-tuned by all possible ways of gene regulation such as epigenetic, transcriptional, post-transcriptional, post-translational, and environmental factors during vertebrate neurogenesis.

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Abbreviations

Hes:

Hairy and enhancer of split

BLBP:

Brain lipid-binding protein

NICD:

Notch intracellular domain

RBP-Jκ:

Recombination signal binding protein for immunoglobulin kappa J region

DAPT:

N-[N-(3,5-difluoro-phenacetyl-l-alanyl]-S-phenylglycine tert-butyl ester

FGF:

Fibroblast growth factor

JNK:

C-Jun N-terminal kinase

ATF2:

Activating transcription factor 2

EGF:

Epidermal growth factor

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinases

Shh:

Sonic hedgehog

AP1:

Activator protein 1

bHLH:

Basic helix-loop-helix

Ngn:

Neurogenin

ES cells:

Embryonic stem cells

BMP:

Bone morphogenetic protein

LIF:

Leukemia inhibitory factor

Jak:

Janus kinase

ROS:

Reactive oxygen species

5-HT1A:

5-Hydroxytryptamine

Tlx3:

T-cell leukemia homeobox protein 3

CDK:

Cyclin-dependent kinase

GABA:

Gamma-aminobutyric acid

miRNA:

microRNA

PDGF:

Platelet-derived growth factor

VEGF:

Vascular endothelial growth factor

RGC:

Retinal ganglion cell

STATs:

Signal transducer and activator of transcription

CNTF:

Ciliary neurotrophic factor

NGF:

Nerve growth factor

TGFβ1:

Transforming growth factor beta 1

Aβ:

Amyloid beta

DNMT:

DNA methyltransferase

DRG:

Dorsal root ganglion

Pax3:

Paired box 3

PI3K:

Phosphatidylinositol 3 kinase

Lhx2:

LIM homeobox 2

VZ:

Ventricular zone

SVZ:

Subventricular zone

CAT:

Chloramphenicol acetyltransferase

TLE:

Transducin-like enhancer of split

NFIA:

Nuclear factor IA

LNA:

Locked nucleic acid

Camk2δ:

Ca2+/calmodulin-dependent protein kinase II delta

PARP-1:

Poly [ADP-ribose] polymerase 1

PKC:

Protein kinase C

DUBs:

Deubiquitinating enzymes

PS1:

Presenilin

DHA:

Docosahexaenoic acid

EPA:

Eicosapentaenoic acid

MAP2:

Microtubule-associated protein 2

GFAP:

Glial fibrillary acidic protein

S100β:

S100 calcium-binding protein Β

CGNs:

Cerebellar granule neurons

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

AD:

Alzheimer’s disease

ZLI:

Zona limitans intrathalamica

CNS:

Central nervous system

PNS:

Peripheral nervous system

NEP:

Neuroepithelial progenitors

Id:

Inhibitors of differentiation

NPC:

Neural progenitor cell

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Acknowledgments

This work was supported by Intramural Grants to J.J. from Rajiv Gandhi Centre for Biotechnology (RGCB) and external funding from Department of Biotechnology, Government of India (BT/PR4919/MED/30/787/2012). S.B.D. (09/716[0126]/2009-EMR-1) and C.S (20-06/2010(i)EU-IV) were supported by research fellowship from Council for Scientific and Industrial Research (CSIR), Government of India.

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  1. Neuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Thiruvananthapuram, 695 014, Kerala, India

    Sivadasan Bindu Dhanesh, Chandramohan Subashini & Jackson James

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Dhanesh, S.B., Subashini, C. & James, J. Hes1: the maestro in neurogenesis. Cell. Mol. Life Sci. 73, 4019–4042 (2016). https://doi.org/10.1007/s00018-016-2277-z

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