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Engrailed 1 deficiency induces changes in ciliogenesis during human neuronal differentiation

ABSTRACT: Engrailed 1 deficiency induces changes in ciliogenesis during human neuronal differentiation

PROVIDER: PRJNA1023165 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26252600_1.fastq.gz	Fastqsanger.gz
	SRR26252600_2.fastq.gz	Fastqsanger.gz
	SRR26252700_1.fastq.gz	Fastqsanger.gz
	SRR26252700_2.fastq.gz	Fastqsanger.gz
	SRR26252601_1.fastq.gz	Fastqsanger.gz

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Engrailed 1 deficiency induces changes in ciliogenesis during human neuronal differentiation

Project description:A key pathological feature of Parkinson's Disease (PD) is the progressive degeneration of dopaminergic neurons (DAns) in the substantia nigra pars compacta. Considering the major role of EN1 in the development and maintenance of these DAns and the implications from En1 mouse models, it is highly interesting to study the molecular and protective effect of EN1 also in a human cellular model. Therefore, we generated EN1 knock-out (ko) human induced pluripotent stem cell (hiPSCs) lines and analyzed these during neuronal differentiation. Although the EN1 ko didn't interfere with neuronal differentiation and generation of tyrosine hydroxylase positive (TH+) neurons per se, the neurons exhibited shorter neurites. Furthermore, mitochondrial respiration, as well as mitochondrial complex I abundance was significantly reduced in fully differentiated neurons. To understand the implications of an EN1 ko during differentiation, we performed a transcriptome analysis of human neuronal precursor cells (hNPCs) which unveiled alterations in cilia-associated pathways. Further analysis of ciliary morphology revealed an elongation of primary cilia in EN1-deficient hNPCs. Besides, also Wnt signaling pathways were severely affected. Upon stimulating hNPCs with Wnt which drastically increased EN1 expression in WT lines, the phenotypes concerning mitochondrial function and cilia were exacerbated in EN1 ko hNPCs. They failed to enhance the expression of the complex I subunits NDUFS1 and 3, and now displayed a reduced mitochondrial respiration. Furthermore, Wnt stimulation decreased ciliogenesis in EN1 ko hNPCs but increased ciliary length even further. This further highlights the relevance of primary cilia next to mitochondria for the functionality and correct maintenance of human DAns and provides new possibilities to establish neuroprotective therapies for PD.

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Ciliogenesis defects after neurulation impact brain development and neuronal activity in larval zebrafish

Project description:Cilia are slender, hair-like structures extending from cell surfaces and playing essential roles in diverse physiological processes. Within the nervous system, primary cilia contribute to signaling and sensory perception, while motile cilia facilitate cerebrospinal fluid flow. Here, we investigated the impact of ciliary loss on neural circuit development using a zebrafish line displaying ciliogenesis defects. We found that cilia defects after neurulation affects neurogenesis and brain morphology, especially in the cerebellum, and lead to altered gene expression profiles. Using whole brain calcium imaging, we measured reduced light-evoked and spontaneous neuronal activity in all brain regions. By shedding light on the intricate role of cilia in neural circuit formation and function in the zebrafish, our work highlights their evolutionary conserved role in the brain and set the stage for future analysis of ciliopathy models.

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Project description:Primary cilia (PCs) are microtubule-based organelles that function as critical signaling hubs in both embryonic neurodevelopment and mature neurons. Tau tubulin kinase 2 (TTBK2) is a key initiator of ciliogenesis, but its role in neuronal regeneration following spinal cord injury (SCI) remains unclear. Here, we investigated whether TTBK2 regulates axonal regeneration and circuit remodeling after SCI via a cilia-dependent mechanism. Using both in vitro spinal neuron cultures and an in vivo conditional knockout (TTBK2^fl/fl-Cre ERT^+/-) mouse model of T10 spinal hemisection, we demonstrate that TTBK2 deletion impairs PC formation, downregulates Sonic Hedgehog (SHH) signaling, reduces MAP2 expression, and disrupts axonal elongation. Overexpression of TTBK2 rescued these deficits, while loss of ciliary function via KIF3A knockdown replicated the phenotypes. Transcriptomic and proteomic profiling revealed that TTBK2 deficiency suppresses axonogenesis-related pathways while enhancing synaptic excitability markers. Notably, activation of SHH signaling by Smoothened agonist partially restored MAP2 expression and axonal growth in TTBK2-deficient neurons. In vivo, TTBK2 knockout mice displayed impaired motor recovery, increased glial scarring, disrupted axonal projection, and elevated expression of axon growth inhibitors (NogoA/NogoR). Confocal imaging and electron microscopy confirmed the loss of PCs and morphological signs of demyelination and aberrant synaptogenesis. Furthermore, endogenous neural stem cells in TTBK2-deficient mice failed to differentiate into mature neurons, correlating with reduced SHH activity. Collectively, our findings identify a TTBK2–PC–SHH–MAP2 regulatory axis that governs axonal regeneration and circuit reassembly after SCI. This study expands the functional relevance of primary cilia beyond neurodevelopment and highlights TTBK2 as a potential therapeutic target for promoting neural repair in the adult CNS.

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Project description:Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, we report that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating a role in the cellular response to the stimulation of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. Our findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.

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