RT Journal Article
SR Electronic
T1 Alternative Splicing of the Histone Demethylase LSD1/KDM1 Contributes to the Modulation of Neurite Morphogenesis in the Mammalian Nervous System
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2521
OP 2532
DO 10.1523/JNEUROSCI.5500-09.2010
VO 30
IS 7
A1 Cristina Zibetti
A1 Antonio Adamo
A1 Claudia Binda
A1 Federico Forneris
A1 Emanuela Toffolo
A1 Chiara Verpelli
A1 Enrico Ginelli
A1 Andrea Mattevi
A1 Carlo Sala
A1 Elena Battaglioli
YR 2010
UL http://www.jneurosci.org/content/30/7/2521.abstract
AB A variety of chromatin remodeling complexes are thought to orchestrate transcriptional programs that lead neuronal precursors from earliest commitment to terminal differentiation. Here we show that mammalian neurons have a specialized chromatin remodeling enzyme arising from a neurospecific splice variant of LSD1/KDM1, histone lysine specific demethylase 1, whose demethylase activity on Lys4 of histone H3 has been related to gene repression. We found that alternative splicing of LSD1 transcript generates four full-length isoforms from combinatorial retention of two identified exons: the 4 aa exon E8a is internal to the amine oxidase domain, and its inclusion is restricted to the nervous system. Remarkably, the expression of LSD1 splice variants is dynamically regulated throughout cortical development, particularly during perinatal stages, with a progressive increase of LSD1 neurospecific isoforms over the ubiquitous ones. Notably, the same LSD1 splice dynamics can be fairly recapitulated in cultured cortical neurons. Functionally, LSD1 isoforms display in vitro a comparable demethylase activity, yet the inclusion of the sole exon E8a reduces LSD1 repressor activity on a reporter gene. Additional distinction among isoforms is supported by the knockdown of neurospecific variants in cortical neurons resulting in the inhibition of neurite maturation, whereas overexpression of the same variants enhances it. Instead, perturbation of LSD1 isoforms that are devoid of the neurospecific exon elicits no morphogenic effect. Collectively, results demonstrate that the arousal of neuronal LSD1 isoforms pacemakes early neurite morphogenesis, conferring a neurospecific function to LSD1 epigenetic activity.