TY  - JOUR
AU  - Xu, Jishu
AU  - Hörner, Michaela
AU  - Nagel, Maike
AU  - Perhat, Perwin
AU  - Korneck, Milena
AU  - Noß, Marvin
AU  - Hauser, Stefan
AU  - Schöls, Ludger
AU  - Admard, Jakob
AU  - Nicolas, Casadei
AU  - Schüle-Freyer, Rebecca
TI  - Unravelling axonal transcriptional landscapes: insights from induced pluripotent stem cell-derived cortical neurons and implications for motor neuron degeneration
JO  - Open biology
VL  - 15
IS  - 6
SN  - 2046-2441
CY  - London
PB  - Royal Society Publishing
M1  - DZNE-2025-00684
SP  - 250101
PY  - 2025
AB  - Neuronal function and pathology are deeply influenced by the distinct molecular profiles of the axon and soma. Traditional studies have often overlooked these differences due to the technical challenges of compartment-specific analysis. In this study, we employ a robust RNA-sequencing approach, using microfluidic devices, to generate high-quality axonal transcriptomes from induced pluripotent stem cells-derived cortical neurons (CNs). We achieve high specificity of axonal fractions, ensuring sample purity without contamination. Comparative analysis revealed a unique and specific transcriptional landscape in axonal compartments, characterized by diverse transcript types, including protein-coding mRNAs, RNAs encoding ribosomal proteins, mitochondrial-encoded RNAs and long non-coding RNAs. Previous works have reported the existence of transcription factors (TFs) in the axon. Here, we detect a set of TFs specific to the axon and indicative of their active participation in transcriptional regulation. To investigate transcripts and pathways essential for central motor neuron (MN) degeneration and maintenance we analysed kinesin family member 1C (KIF1C)-knockout (KO) CNs, modelling hereditary spastic paraplegia, a disorder associated with prominent length-dependent degeneration of central MN axons. We found that several key factors crucial for survival and health were absent in KIF1C-KO axons, highlighting a possible role of these also in other neurodegenerative diseases. Taken together, this study underscores the utility of microfluidic devices in studying compartment-specific transcriptomics in human neuronal models and reveals complex molecular dynamics of axonal biology. The impact of KIF1C on the axonal transcriptome not only deepens our understanding of MN diseases but also presents a promising avenue for exploration of compartment-specific disease mechanisms.
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Induced Pluripotent Stem Cells: cytology
KW  - Axons: metabolism
KW  - Motor Neurons: metabolism
KW  - Motor Neurons: pathology
KW  - Animals
KW  - Mice
KW  - Transcriptome
KW  - Humans
KW  - Gene Expression Profiling
KW  - Transcription Factors: metabolism
KW  - Kinesins: genetics
KW  - Kinesins: metabolism
KW  - Nerve Degeneration: genetics
KW  - Nerve Degeneration: metabolism
KW  - axonal transcriptomics (Other)
KW  - axonal transport (Other)
KW  - iPSC-derived neurons (Other)
KW  - kinesin (Other)
KW  - neurons (Other)
KW  - transcription factors (Other)
KW  - Transcription Factors (NLM Chemicals)
KW  - Kinesins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1098/rsob.250101
UR  - https://pub.dzne.de/record/279124
ER  -