Review article
Neurogenesis impairment: An early developmental defect in Down syndrome

https://doi.org/10.1016/j.freeradbiomed.2017.07.026Get rights and content

Highlights

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    Proliferation potency is highly reduced in the Down syndrome (DS) brain.

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    Acquisition of a neuronal phenotype is reduced in DS.

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    Acquisition of an astrocytic phenotype is enhanced in DS.

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    DYRK1A and APP emerge as key determinants of neurogenesis impairment in DS.

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    This evidence may be exploited to devise therapies for DS.

Abstract

Down syndrome (DS) is characterized by brain hypotrophy and intellectual disability starting from early life stages. Accumulating evidence shows that the phenotypic features of the DS brain can be traced back to the fetal period since the DS brain exhibits proliferation potency reduction starting from the critical time window of fetal neurogenesis. This defect is worsened by the fact that neural progenitor cells exhibit reduced acquisition of a neuronal phenotype and an increase in the acquisition of an astrocytic phenotype. Consequently, the DS brain has fewer neurons in comparison with the typical brain. Although apoptotic cell death may be increased in DS, this does not seem to be the major cause of brain hypocellularity. Evidence obtained in brains of individuals with DS, DS-derived induced pluripotent stem cells (iPSCs), and DS mouse models has provided some insight into the mechanisms underlying the developmental defects due to the trisomic condition. Although many triplicated genes may be involved, in the light of the studies reviewed here, DYRK1A, APP, RCAN1 and OLIG1/2 appear to be particularly important determinants of many neurodevelopmental alterations that characterize DS because their triplication affects both the proliferation and fate of neural precursor cells as well as apoptotic cell death. Based on the evidence reviewed here, pathways downstream to these genes may represent strategic targets, for the design of possible interventions.

Introduction

Down syndrome (DS) is a genetic condition due to triplication of Chromosome 21. The clinical presentation of DS is complex and variable. A few features occur to some degree in every individual with trisomy 21, including characteristic facial dysmorphology, a small and hypocellular brain, and the histopathology of Alzheimer's disease, which is present by the fourth decade. The neurological profile of individuals with DS, which includes intellectual disability, has been associated with brain hypotrophy and hypocellularity. Accumulating evidence shows that the phenotypic features of the DS brain can be traced back to early developmental stages. This review summarizes what is currently known regarding the development of the DS brain and reveals that the DS brain is altered due to impairment of proliferation potency and aberrant phenotype acquisition, starting from the earliest phases of brain development. Based on data obtained in the brains of individuals with DS, DS-derived induced pluripotent stem cells (iPSCs), and DS mouse models, we will highlight the major molecular mechanisms that most likely underlie these alterations. This knowledge may help devise targeted interventions aimed at improving brain development in individuals with DS.

Section snippets

Neurodevelopmental alterations in DS

This section provides comparative information on neuroanatomical defects and neurogenesis alterations (proliferation potency, phenotype acquisition and cell death) in the brains of fetuses/infants/children with DS and DS mouse models during early developmental stages. Regarding the mouse models, we mainly report data at Embryonic (E) and early postnatal (P) stages (P0-P21), because these are periods of intense neurogenesis in rodents.

Mechanisms underlying neurodevelopmental alterations in DS

The mechanisms whereby the DS brain is characterized by reduced proliferation potency and impaired phenotype acquisition (reduced neurogenesis and increased astrogliogenesis) have not been completely dissected, although some mechanisms begin now to be at least partially understood.

Conclusions

The evidence reported above shows that the process of neurogenesis is severely impaired in DS, due to a reduction in the size of the pool of neural progenitor cells starting from the beginning of brain development. This reduction is caused by both an elongation of and a precocious exit from the cell cycle. An increase in apoptotic cell death may also play a role but it appears to contribute more marginally to neurogenesis impairment. The reduced pool of neural progenitor cells exhibits a

Acknowledgments

This work was supported by grants to R. B. from "Fondation Jerome Lejeune", France, “Fondazione Generali e Assicurazioni Generali”, Italy and “Fondazione del Monte”, Italy. The assistance of Melissa Stott in the revision of the language is gratefully acknowledged.

Conflict of interest

The authors declare that they have no conflict of interest.

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