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
Review
. 2021 Feb;141(2):139-158.
doi: 10.1007/s00401-020-02244-5. Epub 2020 Nov 23.

Intellectual disability: dendritic anomalies and emerging genetic perspectives

Tam T Quach  1   2 , Harrison J Stratton  3 , Rajesh Khanna  3 , Pappachan E Kolattukudy  4 , Jérome Honnorat  2   5   6 , Kathrin Meyer  7   8 , Anne-Marie Duchemin  9
Affiliations
Review

Intellectual disability: dendritic anomalies and emerging genetic perspectives

Tam T Quach et al. Acta Neuropathol. 2021 Feb.

Abstract

Intellectual disability (ID) corresponds to several neurodevelopmental disorders of heterogeneous origin in which cognitive deficits are commonly associated with abnormalities of dendrites and dendritic spines. These histological changes in the brain serve as a proxy for underlying deficits in neuronal network connectivity, mostly a result of genetic factors. Historically, chromosomal abnormalities have been reported by conventional karyotyping, targeted fluorescence in situ hybridization (FISH), and chromosomal microarray analysis. More recently, cytogenomic mapping, whole-exome sequencing, and bioinformatic mining have led to the identification of novel candidate genes, including genes involved in neuritogenesis, dendrite maintenance, and synaptic plasticity. Greater understanding of the roles of these putative ID genes and their functional interactions might boost investigations into determining the plausible link between cellular and behavioral alterations as well as the mechanisms contributing to the cognitive impairment observed in ID. Genetic data combined with histological abnormalities, clinical presentation, and transgenic animal models provide support for the primacy of dysregulation in dendrite structure and function as the basis for the cognitive deficits observed in ID. In this review, we highlight the importance of dendrite pathophysiology in the etiologies of four prototypical ID syndromes, namely Down Syndrome (DS), Rett Syndrome (RTT), Digeorge Syndrome (DGS) and Fragile X Syndrome (FXS). Clinical characteristics of ID have also been reported in individuals with deletions in the long arm of chromosome 10 (the q26.2/q26.3), a region containing the gene for the collapsin response mediator protein 3 (CRMP3), also known as dihydropyrimidinase-related protein-4 (DRP-4, DPYSL4), which is involved in dendritogenesis. Following a discussion of clinical and genetic findings in these syndromes and their preclinical animal models, we lionize CRMP3/DPYSL4 as a novel candidate gene for ID that may be ripe for therapeutic intervention.

Keywords: CRMP3/DPYSL4; Chromosome 10 (q26) deletion; Dendrite dysgenesis; Intellectual disability; Transgenic mice.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.. Expression of CRMP3/DPYSL4 during nervous system development and role in cultured hippocampal neurons.
In situ hybridization of CRMP3 in sagittal sections of embryonic and adult mouse brain. (a) At E12.5, transcripts were detected in dorsal root ganglia (drg) and the central nervous system (CNS). Different regions of the rhombencephalon (Rhomb), mesencephalon (Mesen), and diencephalon (Dien) were stained and are denoted with white arrows. The black arrows denoted the CRMP3 expression in the ventricular neuroepithelia and the cortex (Cx). Staining was also observed in cerebellum, which is marked with unfilled arrows. No staining was observed in the choroid plexus (cp). (b). In sections obtained from adult mice, CRMP3 mRNA was detectable mainly in the cerebellar granular layer, the inferior olive, and the dentate gyrus. (c). Summary of In Situ Hybridization with an antisense riboprobe: highly positive signal (+++); weak signal (+). Representative Crmp3−/−cells with no visible processes (d; e) and Crmp3+/− cell with neurites (f; g) using β-galactosidase activity (d; f) or immunostaining with MAP2 antibodies (e; g). Transfected with Fl-CRMP3, neurons are characterized by active transport of the protein, increased formation of lamellipodia, and increased dendritic arborization. Representative CRMP3-over-expressing neuron (h; ov-crmp3) immunostained for Flag (red) and the dendritic marker MAP2 (green). Overlay of image from transfected neurons are in yellow (h, right). Yellow arrows show control (h) or LacZ− (d) cells. White arrows show neurites (f, g).
Figure 2.
Figure 2.. A proposed model for the regulation of dendrite morphology by CRMP3/DPYSL4 activity.
We propose a model involving CRMP3/DPYSL4 activity underlying neurite initiation and dendrite outgrowth following Ca2+ influx. Combinatorial stimulation of CRMP3/DPYSL4 gene expression, or activity by intrinsic and extrinsic factors (1). The localization and distribution of FL-CRMP3-positive puncta in dendrites suggest that CRMP3 could be associated with vesicles or large carrier protein complexes and is then actively transported to dendrites (2). Structural and biochemical studies support the notion that CRMP3 activity might be regulated by phosphorylation or other post-translational modifications (3–4) induced by neurotrophic factors or guidance cues (7). Activated CRMP3/DPYSL4 binds to protein partners and serves as an adaptor in a variety of signaling pathways including Ca2+ influx (CaV; 5). Our genetic studies have shown that CRMP3/DPYSL4 contributes to dendritic arborization, dendritic spine genesis (6) and neurite initiation (8). These effects might involve lamellipodia formation, cell migration (9), dendritic arborization, spine density and structure. Collectively, these functional clusters may affect cognition, learning and memory (10).
Figure 3.
Figure 3.. Schematic representation of gene distribution on chromosome 10.
Mapping the q26 terminal area (a) and the genes involved in brain disorders (b).
Figure 4.
Figure 4.. Dendritic tree and spine morphology changes associated with intellectual ability.
The model depicts a pyramidal neuron displaying high dendritic spine density, which is correlated with higher levels of intelligence. Lower scores on the IQ assessment, < 70, are associated with lower dendritic arbor complexity as well as decreased spine density in numerous brain regions. These morphological characteristics are highly correlated with scores on the IQ assessment and likely underlie the functional outcomes associated with ID.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aizawa H, Hu SC, Bobb K, Balakrishnan K, Ince G, Gurevich I, Cowan M, Ghosh A (2004) Dendrite development regulated by CREST, a calcium-regulated transcriptional activator. Science 303:197–202. 10.1126/science.1089845. - DOI - PubMed
    1. Akum BF, Chen M, Gunderson SI, Riefler GM, Scerri-Hansen MM, Firestein BL (2004) Cypin regulates dendrite patterning in hippocampal neurons by promoting microtubule assembly. Nat Neurosci 7:145–52. 10.1038/nn1179. - DOI - PubMed
    1. Aldosary M, Al-Bakheet A, Al-Dhalaan H, Almass R, Alsagob M, Al-Younes B, AlQuait L, Mustafa OM, Bulbul M, Rahbeeni Z, Alfadhel M, Chedrawi A, Al-Hassnan Z, AlDosari M, Al-Zaidan H, Al-Muhaizea MA, AlSayed MD, Salih MA, AlShammari M, Faiyaz-Ul-Haque M, Chishti MA, Al-Harazi O, Al-Odaib A, Kaya N, Colak D (2020) Rett Syndrome, a Neurodevelopmental Disorder, Whole-Transcriptome, and Mitochondrial Genome Multiomics Analyses Identify Novel Variations and Disease Pathways. OMICS 24:160–171. 10.1089/omi.2019.0192. - DOI - PubMed
    1. Alimi A, Lauren A, Weeth-Feinstein LA, Stettner A , Caldera F, Weiss JM (2015) Overlap of Juvenile Polyposis Syndrome and Cowden Syndrome Due to De Novo Chromosome 10 Deletion Involving BMPR1A and PTEN: Implications for Treatment - PMC - PubMed
    1. Alves-Sampaio A, Troca-Marín JA, Montesinos ML (2010) NMDA-mediated regulation of DSCAM dendritic local translation is lost in a mouse model of Down's syndrome. J Neurosci. 30:13537–48. 10.1523/JNEUROSCI.3457-10.2010. - DOI - PMC - PubMed

Publication types

Substances

LinkOut - more resources