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A human-specific microRNA controls the timing of excitatory synaptogenesis

ABSTRACT: The development of neural circuits in the human cortex is considerably prolonged in comparison to non-human primates, a trait which contributes to the remarkable cognitive capacity of modern humans. In contrast to protein-coding genes, non-coding genes underwent a dramatic expansion during evolution, suggesting their involvement in human-specific aspects of brain development. Here, using a glial free human-induced pluripotent stem-cell derived neuron model (“igNeurons”), we show widespread expression and dynamic regulation of various non-coding RNA classes, including microRNAs, during human excitatory synapse development. The expression of a human-specific microRNA, miR-1229-3p, strongly correlates with the neuromorphological trajectory of igNeurons. miR-1229-3p inhibition promotes the formation of excitatory synaptic co-clusters at early stages but reduces dendritic arborization in more mature neurons, consistent with accelerated neuronal maturation. Morphological alterations are accompanied by enhanced calcium spike activity and excitatory synaptic transmission. Mechanistically, miR-1229-3p controls mitochondrial homeostasis by directly targeting important regulators of mitochondrial autophagy and fission, such as Pink1. Stimulation of mitochondrial metabolism rescues the enhanced calcium spike activity in miR-1229-3p depleted neurons, demonstrating a causal involvement of mitochondrial homeostasis. Thus, our findings reveal an important function of human-specific miR-1229-3p in developmental timing of human synaptogenesis and generally implicate non-coding RNAs in the control of human connectivity and cognition.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Neuron, Cell Culture

SUBMITTER: Michael Soutschek

LAB HEAD: Gerhard Schratt

PROVIDER: PXD045809 | Pride | 2025-11-03

REPOSITORIES: Pride

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			Action	DRS
	20191206_002_S209921_iPSC_Neuron_Screen_1_SC3_27_re4ul.raw	Raw
	20191206_003_S209922_iPSC_Neuron_Screen_2_SC3_21.raw	Raw
	20191206_004_S209923_iPSC_Neuron_Screen_3_SC3_9.raw	Raw
	20191206_006_S209924_iPSC_Neuron_Screen_4_SC3_0.raw	Raw
	20191206_007_S209925_iPSC_Neuron_Screen_5_SC3_15.raw	Raw

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Project description:Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ~1:200-500 and predisposes individuals to sudden death and heart failure. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and Results: Using high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured primary cardiac non-myocytes and analyzed the conditioned media by proteomics, we found that several ECM proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially expressed. We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac non-myocytes drives upregulation of ECM genes including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac non-myocytes. Conclusions: Altogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac non-myocytes. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.

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A human-specific microRNA controls the timing of excitatory synaptogenesis

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