Table 1.

Overview of lncRNAs roles in each non-syndromic intellectual disability-related pathway.

Pathway	LncRNA	Ensembl Gene ID	Biotype 1	Role in the Pathway	Reference
Wnt/β-catenin pathway	MEG3	ENSG00000214548	Intergenic	It modulates the Wnt/β-catenin signaling pathway, enhancing nerve growth and alleviating neurological impairment of rats after brain injury.	[46]
	Neat1	ENSG00000245532	Intergenic	The signaling axis miR-124-Neat1-Wnt/β-catenin plays an important role in regulating neuronal differentiation, apoptosis, and migration of mouse spinal cord progenitor cells.	[48]
	RMST	ENSG00000255794	Intergenic	Nuclear lncRNA RMST regulates neuronal differentiation and associates with transcription factor SOX2.	[51]
	Sox2ot	ENSG00000242808	Sense overlapping	Its expression is inversely correlated to Sox2 expression during neural differentiation of mouse ESCs.	[52]
	lincRNA-RoR	ENSG00000258609	Intergenic	lincRNA-RoR participates in a regulatory loop, together with Sox2, to help maintain hESC self-renewal balance and may contribute to genetic networks’ regulation during development.	[53]
	Gomafu	ENSG00000225783	Intergenic	The long non-coding RNA Gomafu induces alternative splicing of DISC1, leading to its downregulation and disturbing neurodevelopmental mechanisms.	[45,56]
Notch	LncND	NA	Intergenic	It sequesters miR-143-3p, which targets NOTCH1 and NOTCH2 mRNAs. Knockdown of this lncRNA led to premature precursor cells’ differentiation in humans and its overexpression regulates radial glial cells’ expansion in murine developing cortex.	[64]
	KANTR	ENSG00000232593	Sense overlapping/Sense intronic	Knockout mice of KANTR locus increased gene sets involved in Notch signaling and neural development.	[65]
	PERIL	NA	NA	Knockout mice of these lncRNAs locus increased the neural stem cell marker genes NOTCH1–3.	[65]
	PANTR1	ENSG00000233639	Intergenic
	XIST	ENSG00000229807	Intergenic	XIST silencing of the extra chr21 in Down Syndrome hiPSCs led to diminished Notch pathway signaling and a higher rate of neuron production.	[66]
Sonic hedgehog	AK053922	NA	NA	It helps to specify distinct neuronal cell types through acting as a bifunctional transcriptional switch that can either repress or activate sonic hedgehog (Shh) signaling.	[77,78]
	Gm15577	ENSMUSG00000086708	Antisense	In mice, it modulates Shh mRNA expression, playing important roles in neuronal growth and neuroplasticity.	[80]
	Evf2/DLX6-AS1	ENSG00000231764	Antisense	Evf2 is required for proper GABAergic interneuron development, through a transcriptional cascade initiated by Shh signaling in the embryonic ventral forebrain.	[82,86]
Growth and neurotrophic factors	BDNF-AS	ENSG00000245573	Antisense	Regulates BDNF mRNA and protein levels, which are critical for the development, survival, and maintenance of neurons in the nervous system.	[109,110]
	MIAT/Gomafu	ENSG00000225783	Intergenic	It is involved in brain development and regulation of neural and vascular cell function via the Gomafu/miR-150-5p/VEGF network.	[111,112]
MAPK/ERK	LoNA	NA	NA	Knockdown of LoNA led to an increase of NR1, NR2A, and NR2B proteins in mice and was found in association with improved neuronal plasticity and long-term potentiation.	[135]
	SYNGAP1-AS1	ENSG00000274259	Antisense	SYNGAP1-AS is supposed to regulate the expression of SYNGAP1 mRNA in the prefrontal cortex and superior temporal gyrus of patients with autism spectrum disorders.	[137]
	MALAT1	ENSG00000251562	Intergenic	Knockdown of MALAT1 resulted in the inhibition of the MAPK/ERK pathway in mouse N2a cells and also could inhibit this signaling pathway in a rat model of cerebral infarction.	[149,150]
	LINC-PINT	ENSG00000231721	Intergenic	In mice, its homologous (LincPint) regulates genes of the MAPK pathway and its transcription is hampered by MEK inhibition in the murine hippocampus. In human normal tissues, the expression of LINC-PINT was positively correlated with the expression of the MAPK pathway genes.	[151,152]
	Neat1	ENSG00000245532	Intergenic	This transcript is processed into two isoforms that are involved in the pathogenesis of human neurodegenerative diseases and, in mice, its alternatively spliced variants are differentially regulated by the MAPK/ERK pathway.	[157]
Synaptic vesicle trafficking and exocytosis	SNAP25-AS1	ENSG00000227906	Antisense	In ASD patients, it is upregulated and associated with the synaptic vesicle cycling pathway.	[21]
	NeuroLNC	NA	NA	It interacts with TDP-43, affecting synaptic vesicle release, which may be the cause of disrupted neuro-trafficking in amyotrophic lateral sclerosis.	[168]
Transcriptional regulation and chromatin remodeling	FMR4	ENSG00000268066	Antisense	The FMR4-mediated histone changes affected the expression of neurodevelopmental genes and its targets may be related to its function as a positive regulator of neural precursor cell proliferation.	[18]
	Dali	NA	Intergenic	Dali controls the expression of the transcription factor gene Pou3f3 (also known as BRN1 or Oct8), which in turn plays a role in the development of the nervous system.	[177]
	RNCR3	ENSG00000253230	Intergenic	Physical association of MECP2 with the lncRNA RNCR3 confers new mechanisms of gene regulation by affecting chromatin structure.	[181]
	Pnky	ENSMUSG00000107859	NA	It regulates neuronal differentiation of embryonic and postnatal neural stem cells by binding to the PTBP1 protein.	[17,182]
	Tuna	ENSG00000250366	Intronic	The lncRNA Tuna binds to PTBP1, with a possible role in neurogenesis. However, the mechanism needs to be further investigated.	[183]
	MIAT	ENSG00000225783	Intergenic	It is involved in a neurogenic commitment by controlling the differentiation of neural progenitors and the survival of newborn neurons.	[185]
	CAT7	NA	NA	CAT7 cooperates with PRC1 to promote gene regulation during neuronal differentiation.	[186]
	lnc-Nr2f1	ENSG00000248588	Antisense	lnc-Nr2f1 binds to chromatin in an isoform-specific way to distinct genomic loci, regulating neuronal genes in mice.	[22]

¹ Biotypes were obtained with the LNCipedia database (https://lncipedia.org/, accessed on 11 November 2020). NA: Not available.