RUES2 cell lines represent the first collection of isogenic human embryonic stem cells (hESCs) carrying different pathological CAG lengths in the HTT gene. However, their neuronal differentiation potential has yet to be thoroughly evaluated. Here, we report that RUES2 during ventral telencephalic differentiation is biased towards medial ganglionic eminence (MGE). We also show that HD-RUES2 cells exhibit an altered MGE transcriptional signature in addition to recapitulating known HD phenotypes, with reduced expression of the neurodevelopmental regulators NEUROD1 and BDNF and increased cleavage of synaptically enriched N-cadherin. Finally, we identified the transcription factor SP1 as a common potential detrimental co-partner of muHTT by de novo motif discovery analysis on the LGE, MGE, and cortical genes differentially expressed in HD human pluripotent stem cells in our and additional datasets. Taken together, these observations suggest a broad deleterious effect of muHTT in the early phases of neuronal development that may unfold through its altered interaction with SP1.

RUES2 hESCs exhibit MGE-biased neuronal differentiation and muHTT-dependent defective specification hinting at SP1 / P. Conforti, D. Besusso, S. Brocchetti, I. Campus, C. Cappadona, M. Galimberti, A. Laporta, R. Iennaco, R.L. Rossi, V. Bocchi, E. Cattaneo. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 146(2020 Dec).

RUES2 hESCs exhibit MGE-biased neuronal differentiation and muHTT-dependent defective specification hinting at SP1

P. Conforti
Primo
;
D. Besusso
Secondo
;
S. Brocchetti;I. Campus;C. Cappadona;M. Galimberti;A. Laporta;R. Iennaco;V. Bocchi
Penultimo
;
E. Cattaneo
Ultimo
2020-12

Abstract

RUES2 cell lines represent the first collection of isogenic human embryonic stem cells (hESCs) carrying different pathological CAG lengths in the HTT gene. However, their neuronal differentiation potential has yet to be thoroughly evaluated. Here, we report that RUES2 during ventral telencephalic differentiation is biased towards medial ganglionic eminence (MGE). We also show that HD-RUES2 cells exhibit an altered MGE transcriptional signature in addition to recapitulating known HD phenotypes, with reduced expression of the neurodevelopmental regulators NEUROD1 and BDNF and increased cleavage of synaptically enriched N-cadherin. Finally, we identified the transcription factor SP1 as a common potential detrimental co-partner of muHTT by de novo motif discovery analysis on the LGE, MGE, and cortical genes differentially expressed in HD human pluripotent stem cells in our and additional datasets. Taken together, these observations suggest a broad deleterious effect of muHTT in the early phases of neuronal development that may unfold through its altered interaction with SP1.
Huntington's disease; Isogenic cell lines; Neurodegeneration; Neuronal specification; Pluripotent stem cell; SP1; Striatal differentiation
Settore BIO/14 - Farmacologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/793278
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