Altevogt, P., Ben-Ze’ev, A., Gavert, N., Schumacher, U., Scha¨fer, H.,
and Sebens, S. (2020). Recent insights into the role of L1CAM in
cancer initiation and progression. Int. J. Cancer 147, 3292–3296.
Statistical analysis
Aschauer, D.F., Kreuz, S., and Rumpel, S. (2013). Analysis of transduction efficiency, tropism and axonal transport of AAV serotypes
1, 2, 5, 6, 8 and 9 in the mouse brain. PLoS One 8, e76310.
Statistical analyses were performed using Prism 9 (GraphPad Software). For comparisons in the in vivo experiment, the significances
of differences were determined using Mann-Whitney test for com-
Asokan, A., Schaffer, D.V., and Samulski, R.J. (2012). The AAV vector toolkit: poised at the clinical crossroads. Mol. Ther. 20,
699–708.
912 Stem Cell Reports j Vol. 18 j 899–914 j April 11, 2023
¨ schel, A.W., and Bolz, J.
Bagnard, D., Lohrum, M., Uziel, D., Pu
(1998). Semaphorins act as attractive and repulsive guidance signals during the development of cortical projections. Development
125, 5043–5053.
Balaian, L.B., Moehler, T., and Montgomery, A.M. (2000). The human neural cell adhesion molecule L1 functions as a costimulatory
molecule in T cell activation. Eur. J. Immunol. 30, 938–943.
Barry, J., Gu, Y., and Gu, C. (2010). Polarized targeting of L1-CAM
regulates axonal and dendritic bundling in vitro. Eur. J. Neurosci.
32, 1618–1631.
Boyer, N.P., and Gupton, S.L. (2018). Revisiting netrin-1: one who
guides (axons). Front. Cell. Neurosci. 12, 221.
Burda, J.E., and Sofroniew, M.V. (2014). Reactive gliosis and the
multicellular response to CNS damage and disease. Neuron 81,
229–248.
Burden-Gulley, S.M., Pendergast, M., and Lemmon, V. (1997). The
role of cell adhesion molecule L1 in axonal extension, growth cone
motility, and signal transduction. Cell Tissue Res. 290, 415–422.
Canty, A.J., and Murphy, M. (2008). Molecular mechanisms of
axon guidance in the developing corticospinal tract. Prog. Neurobiol. 85, 214–235.
Cohen, N.R., Taylor, J.S., Scott, L.B., Guillery, R.W., Soriano, P., and
Furley, A.J. (1998). Errors in corticospinal axon guidance in mice
lacking the neural cell adhesion molecule L1. Curr. Biol. 8, 26–33.
Colombo, F., and Meldolesi, J. (2015). L1-CAM and N-CAM: from
adhesion proteins to pharmacological targets. Trends Pharmacol.
Sci. 36, 769–781.
Domı´nguez-Romero, M.E., and Slater, P.G. (2021). Unraveling
axon guidance during axotomy and regeneration. Int. J. Mol. Sci.
22, 8344.
Gaillard, A., Prestoz, L., Dumartin, B., Cantereau, A., Morel, F.,
Roger, M., and Jaber, M. (2007). Reestablishment of damaged adult
motor pathways by grafted embryonic cortical neurons. Nat. Neurosci. 10, 1294–1299.
control of axon growth and guidance. Annu. Rev. Neurosci. 26,
509–563.
Kamiguchi, H., and Lemmon, V. (1997). Neural cell adhesion molecule L1: signaling pathways and growth cone motility. J. Neurosci.
Res. 49, 1–8.
Kim, S.-I., Oceguera-Yanez, F., Sakurai, C., Nakagawa, M., Yamanaka, S., and Woltjen, K. (2015). Inducible transgene expression
in human iPS cells using versatile all-in-one piggyBac transposons.
In Methods in Molecular Biology (Humana Presspp), pp. 111–131.
Kitahara, T., Sakaguchi, H., Morizane, A., Kikuchi, T., Miyamoto, S.,
and Takahashi, J. (2020). Axonal extensions along corticospinal
tracts from transplanted human cerebral organoids. Stem Cell
Rep. 15, 467–481.
Lemmon, V., Farr, K.L., and Lagenaur, C. (1989). L1-mediated axon
outgrowth occurs via a homophilic binding mechanism. Neuron
2, 1597–1603.
Lemon, R.N. (2008). Descending pathways in motor control.
Annu. Rev. Neurosci. 31, 195–218.
Lemon, R.N., Landau, W., Tutssel, D., and Lawrence, D.G. (2012).
Lawrence and Kuypers (1968a,b) revisited Copies of the original
filmed material from their classic papers in Brain. Brain 135,
2290–2295.
Lepore, A.C. (2011). Intraspinal cell transplantation for targeting
cervical ventral horn in amyotrophic lateral sclerosis and traumatic spinal cord injury. J. Vis. Exp. 55, 3069.
Leyva-Dı´az, E., and Lo´pez-Bendito, G. (2013). In and out from the
cortex: development of major forebrain connections. Neuroscience 254, 26–44.
Lisowski, L., Tay, S.S., and Alexander, I.E. (2015). Adeno-associated
virus serotypes for gene therapeutics. Curr. Opin. Pharmacol. 24,
59–67.
Lowery, L.A., and Van Vactor, D. (2009). The trip of the tip: understanding the growth cone machinery. Nat. Rev. Mol. Cell Biol. 10,
332–343.
Giger, R.J., Hollis, E.R., and Tuszynski, M.H. (2010). Guidance molecules in axon regeneration. Cold Spring Harb. Perspect. Biol. 2,
a001867.
Maten, M.v.d., Reijnen, C., Pijnenborg, J.M.A., and Zegers, M.M.
(2019). L1 cell adhesion molecule in cancer, a systematic review
on domain-specific functions. Int. J. Mol. Sci. 20, 4180.
Grade, S., and Go¨tz, M. (2017). Neuronal replacement therapy: previous achievements and challenges ahead. Npj Regen. Med. 2, 29.
Mecollari, V., Nieuwenhuis, B., and Verhaagen, J. (2014). A
perspective on the role of class iii semaphorin signaling in central
nervous system trauma. Front. Cell. Neurosci. 8, 328.
Grumet, M. (2003). The L1CAM extracellular region a multidomain protein with modular and cooperative binding modes.
Front. Biosci. 8, s1210–s1225.
Haery, L., Deverman, B.E., Matho, K.S., Cetin, A., Woodard, K.,
Cepko, C., Guerin, K.I., Rego, M.A., Ersing, I., Bachle, S.M., et al.
(2019). Adeno-associated virus technologies and methods for targeted neuronal manipulation. Front. Neuroanat. 13, 93.
Hlavin, M.L., and Lemmon, V. (1991). Molecular structure and
functional testing of human L1CAM: an interspecies comparison.
Genomics 11, 416–423.
Hortsch, M. (2000). Structural and functional evolution of the L1
family: are four adhesion molecules better than one? Mol. Cell.
Neurosci. 15, 1–10.
Huber, A.B., Kolodkin, A.L., Ginty, D.D., and Cloutier, J.-F. (2003).
Signaling at the growth cone: ligand-receptor complexes and the
Me´tin, C., Dele´glise, D., Serafini, T., Kennedy, T.E., and Tessier-Lavigne, M. (1997). A role for netrin-1 in the guidance of cortical efferents. Development 124, 5063–5074.
Nieuwenhuis, B., Haenzi, B., Hilton, S., Carnicer-Lombarte, A.,
Hobo, B., Verhaagen, J., and Fawcett, J.W. (2021). Optimization
of adeno-associated viral vector-mediated transduction of the corticospinal tract: comparison of four promoters. Gene Ther. 28,
56–74.
Pasterkamp, R.J., and Verhaagen, J. (2006). Semaphorins in axon
regeneration: developmental guidance molecules gone wrong?
Philos. Trans. R. Soc. Lond. B Biol. Sci. 361, 1499–1511.
Pe´ron, S., Droguerre, M., Debarbieux, F., Ballout, N., Benoit-Marand, M., Francheteau, M., Brot, S., Rougon, G., Jaber, M., and Gaillard, A. (2017). A delay between motor cortex lesions and neuronal
Stem Cell Reports j Vol. 18 j 899–914 j April 11, 2023 913
transplantation enhances graft integration and improves repair
and recovery. J. Neurosci. 37, 1820–1834.
Samata, B., Takaichi, R., Ishii, Y., Fukushima, K., Nakagawa, H.,
Ono, Y., and Takahashi, J. (2020). L1CAM is a marker for enriching
corticospinal motor neurons in the developing brain. Front. Cell.
Neurosci. 14, 31.
Scha¨fer, M.K.E., and Frotscher, M. (2012). Role of L1CAM for axon
sprouting and branching. Cell Tissue Res. 349, 39–48.
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair,
M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B.,
et al. (2012). Fiji: an open-source platform for biological-image
analysis. Nat. Methods 9, 676–682.
Susaki, E.A., Tainaka, K., Perrin, D., Yukinaga, H., Kuno, A., and
Ueda, H.R. (2015). Advanced CUBIC protocols for whole-brain
and whole-body clearing and imaging. Nat. Protoc. 10, 1709–1727.
Tervo, D.G.R., Hwang, B.-Y., Viswanathan, S., Gaj, T., Lavzin, M.,
Ritola, K.D., Lindo, S., Michael, S., Kuleshova, E., Ojala, D., et al.
(2016). A designer AAV variant permits efficient retrograde access
to projection neurons. Neuron 92, 372–382.
Wang, X., Liu, Y., Li, X., Zhang, Z., Yang, H., Zhang, Y., Williams,
P.R., Alwahab, N.S.A., Kapur, K., Yu, B., et al. (2017). Deconstruction of corticospinal circuits for goal-directed motor skills. Cell
171, 440–455.e14.
Stoeckli, E.T. (2018). Understanding axon guidance: are we nearly
there yet? Development 145, dev151415.
Watakabe, A., Ohtsuka, M., Kinoshita, M., Takaji, M., Isa, K., Mizukami, H., Ozawa, K., Isa, T., and Yamamori, T. (2015). Comparative analyses of adeno-associated viral vector serotypes 1, 2, 5, 8
and 9 in marmoset, mouse and macaque cerebral cortex. Neurosci.
Res. 93, 144–157.
Susaki, E.A., Tainaka, K., Perrin, D., Kishino, F., Tawara, T., Watanabe, T.M., Yokoyama, C., Onoe, H., Eguchi, M., Yamaguchi, S.,
et al. (2014). Whole-brain imaging with single-cell resolution using chemical cocktails and computational analysis. Cell 157,
726–739.
Wolterink, S., Moldenhauer, G., Fogel, M., Kiefel, H., Pfeifer, M.,
¨ ttgau, S., Gouveia, R., Costa, J., Endell, J., Moebius, U., et al.
Lu
(2010). Therapeutic antibodies to human L1CAM: functional characterization and application in a mouse model for ovarian carcinoma. Cancer Res. 70, 2504–2515.
Sharma, A., Verhaagen, J., and Harvey, A.R. (2012). Receptor complexes for each of the class 3 Semaphorins. Front. Cell. Neurosci. 6,
1–13.
914 Stem Cell Reports j Vol. 18 j 899–914 j April 11, 2023
...