Age-maintained human neurons demonstrate a developmental loss of intrinsic neurite growth ability

Lear, B. P.; Thompson, E. A. N.; Rodriguez, K.; Arndt, Z. P.; Khullar, S.; Klosa, P. C.; Lu, R. J.; Morrow, C. S.; Risgaard, R.; Peterson, E. R.; Teefy, B. B.; Bhattacharyya, A.; Sousa, A. M. M.; Wang, D.; Benayoun, B. A.; Moore, D. L.

doi:10.1101/2023.05.23.541995

bioRxiv · 10.1101/2023.05.23.541995

Age-maintained human neurons demonstrate a developmental loss of intrinsic neurite growth ability

Lear, B. P.·Thompson, E. A. N.·Rodriguez, K.·Arndt, Z. P.·Khullar, S.·Klosa, P. C.·Lu, R. J.·Morrow, C. S.·Risgaard, R.·Peterson, E. R.·Teefy, B. B.·Bhattacharyya, A.·Sousa, A. M. M.·Wang, D.·Benayoun, B. A.·Moore, D. L.

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Abstract

Injury to adult mammalian central nervous system (CNS) axons results in limited regeneration. Rodent studies have revealed a developmental switch in CNS axon regenerative ability, yet whether this is conserved in humans is unknown. Using human fibroblasts from 8 gestational-weeks to 72 years-old, we performed direct reprogramming to transdifferentiate fibroblasts into induced neurons (Fib-iNs), avoiding pluripotency which restores cells to an embryonic state. We found that early gestational Fib-iNs grew longer neurites than all other ages, mirroring the developmental switch in regenerative ability in rodents. RNA-sequencing and screening revealed ARID1A as a developmentally-regulated modifier of neurite growth in human neurons. These data suggest that age-specific epigenetic changes may drive the intrinsic loss of neurite growth ability in human CNS neurons during development. One-Sentence Summary: Directly-reprogrammed human neurons demonstrate a developmental decrease in neurite growth ability.

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Lear, B. P., Thompson, E. A. N., Rodriguez, K., Arndt, Z. P., Khullar, S., Klosa, P. C., Lu, R. J., Morrow, C. S., Risgaard, R., Peterson, E. R., Teefy, B. B., Bhattacharyya, A., Sousa, A. M. M., Wang, D., Benayoun, B. A., Moore, D. L.. 2023-05-24. Age-maintained human neurons demonstrate a developmental loss of intrinsic neurite growth ability. https://doi.org/10.1101/2023.05.23.541995

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