---
OA_place: repository
OA_type: green
_id: '21290'
abstract:
- lang: eng
text: Gene duplication underlies evolutionary innovation, yet many paralogues remain
highly similar, raising questions about their functional divergence and physiological
relevance. The spliceosomal Sm core protein SNRPB and its mammalian-specific paralogue
SNRPN share over 90% sequence identity, but their distinct expression patterns
- SNRPB being ubiquitous and SNRPN confined to the brain - suggest specialized
functions. Why mammals have two different spliceosomes has remained obscure. Here,
we generated isogenic human cell lines expressing ectopically either SNRPB or
SNRPN exclusively and found that SNRPN stabilizes transcripts involved in energy
metabolism and mitochondrial function, leading to increased mitochondrial abundance
and oxygen consumption. Despite similar spliceosomal interactomes, SNRPN more
strongly associates with the PRMT5 methylosome complex and exhibits dynamic arginine
methylation in its C-terminal region that is sensitive to translation inhibition
and amino acid availability. The SNRPN-dependent transcriptome responds to translation
inhibition by stabilizing long, intron-rich genes involved in amino acid and energy
metabolism. Our findings reveal a nutrient-sensitive, methylation-dependent mechanism
that differentiates the two paralogues. This suggests that SNRPN functions as
a metabolic-specialized spliceosomal subunit thereby providing tissue-specific
adaptation of RNA processing in mammals.
acknowledgement: "We thank Oliver Mühlemann and Alex Hofer (University of Bern) for
sharing SMG inhibitors\r\nand for their expertise in nonsense-mediated mRNA decay
and Maria Hondele for critical\r\nreading of the manuscript draft. We also thank
the IMB Genomics Core Facility for assistance\r\nwith library preparation and sequencing,
Martin Möckel and the IMB Protein Production Core\r\nFacility for providing enzymes
used in this work, Marton Gelleri together with the IMB\r\nMicroscopy Core Facility
for support with microscopy and FRAP experiments, Jasmin Cartano\r\nfor proteomics
sample processing and the IMB Flow Cytometry Core Facility for support. In\r\naddition,
we thank the Imaging Core Facility (IMCF) and the FACS Core Facility at the\r\nBiozentrum,
University of Basel, for technical assistance. CIKV acknowledges funding by the\r\nDeutsche
Forschungsgemeinschaft (DFG, German Research Foundation) - Individual Grant\r\nProject
no. 513744403, Scientific Network Grant Project no. 531902894, GRK2526 “Genevo”\r\n-
Project no. 407023052”, GRK2859 (“4R”) - Project no. 491145305, Forschungsinitiative\r\nRheinland-Pfalz
(ReALity), the EMBO Young Investigator Program (5795), institutional\r\nfunding
from the Institute of Molecular Biology and funds from the Kanton Basel-Stadt and\r\nBasel-Land
provided to the Biozentrum of the University Basel. J.H.G.F.G. was part of the\r\n‘Science
of Healthy Ageing Research Programme’ (SHARP) initiative funded by RhinelandPalatinate’s
Ministry of Science, Education and Culture. PR is funded by the Biozentrum PhD\r\nFellowships
Program. MFB received financial support from the intramural High Potentials\r\nGrant
program of the University Medical Center Mainz, Forschungsinitiative Rheinland-Pfalz\r\n(ReALity)
and Stiftungen zugunsten der Medizinischen Fakultät der LMU Klinikum (26069).\r\nInstruments
in the IMB core facilities were supported by funds from the DFG: Laser Scanning\r\nConfocal
(Leica Stellaris 8 Falcon, funded by the DFG - Project #497669232), Orbitrap Astral
system (funded by the DFG - Project #524805621) and BD LSRFortessa SOPR is funded
by\r\nthe DFG - Project #210253511.\r\n"
article_processing_charge: No
author:
- first_name: Feyza
full_name: Polat Haas, Feyza
last_name: Polat Haas
- first_name: Ana
full_name: Villalba Requena, Ana
id: 68cb85a0-39f7-11eb-9559-9aaab4f6a247
last_name: Villalba Requena
orcid: 0000-0002-5615-5277
- first_name: Polina
full_name: Rusina, Polina
last_name: Rusina
- first_name: Anusha
full_name: Gopalan, Anusha
last_name: Gopalan
- first_name: Hector
full_name: Fritz, Hector
last_name: Fritz
- first_name: Azamat
full_name: Akhmetkaliyev, Azamat
last_name: Akhmetkaliyev
- first_name: Frank
full_name: Ruehle, Frank
last_name: Ruehle
- first_name: Anna
full_name: Einsiedel, Anna
last_name: Einsiedel
- first_name: Anna
full_name: Szczepinska, Anna
last_name: Szczepinska
- first_name: Fridolin
full_name: Kielisch, Fridolin
last_name: Kielisch
- first_name: Jia-Xuan
full_name: Chen, Jia-Xuan
last_name: Chen
- first_name: Susanne
full_name: Nguyen, Susanne
last_name: Nguyen
- first_name: Thierry
full_name: Schmidlin, Thierry
last_name: Schmidlin
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
- first_name: M. Felicia
full_name: Bailicata, M. Felicia
last_name: Bailicata
- first_name: Claudia Isabelle
full_name: Keller Valsecchi, Claudia Isabelle
last_name: Keller Valsecchi
citation:
ama: Polat Haas F, Villalba Requena A, Rusina P, et al. The splicing paralogues
SNRPB and SNRPN control differential metabolic states. bioRxiv. doi:10.64898/2026.02.11.705284
apa: Polat Haas, F., Villalba Requena, A., Rusina, P., Gopalan, A., Fritz, H., Akhmetkaliyev,
A., … Keller Valsecchi, C. I. (n.d.). The splicing paralogues SNRPB and SNRPN
control differential metabolic states. bioRxiv. https://doi.org/10.64898/2026.02.11.705284
chicago: Polat Haas, Feyza, Ana Villalba Requena, Polina Rusina, Anusha Gopalan,
Hector Fritz, Azamat Akhmetkaliyev, Frank Ruehle, et al. “The Splicing Paralogues
SNRPB and SNRPN Control Differential Metabolic States.” BioRxiv, n.d. https://doi.org/10.64898/2026.02.11.705284.
ieee: F. Polat Haas et al., “The splicing paralogues SNRPB and SNRPN control
differential metabolic states.,” bioRxiv. .
ista: Polat Haas F, Villalba Requena A, Rusina P, Gopalan A, Fritz H, Akhmetkaliyev
A, Ruehle F, Einsiedel A, Szczepinska A, Kielisch F, Chen J-X, Nguyen S, Schmidlin
T, Hippenmeyer S, Bailicata MF, Keller Valsecchi CI. The splicing paralogues SNRPB
and SNRPN control differential metabolic states. bioRxiv, 10.64898/2026.02.11.705284.
mla: Polat Haas, Feyza, et al. “The Splicing Paralogues SNRPB and SNRPN Control
Differential Metabolic States.” BioRxiv, doi:10.64898/2026.02.11.705284.
short: F. Polat Haas, A. Villalba Requena, P. Rusina, A. Gopalan, H. Fritz, A. Akhmetkaliyev,
F. Ruehle, A. Einsiedel, A. Szczepinska, F. Kielisch, J.-X. Chen, S. Nguyen, T.
Schmidlin, S. Hippenmeyer, M.F. Bailicata, C.I. Keller Valsecchi, BioRxiv (n.d.).
date_created: 2026-02-17T11:35:59Z
date_published: 2026-02-11T00:00:00Z
date_updated: 2026-02-23T11:03:33Z
day: '11'
department:
- _id: SiHi
doi: 10.64898/2026.02.11.705284
fulldoi: https://doi.org/10.64898/2026.02.11.705284
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.64898/2026.02.11.705284
month: '02'
oa: 1
oa_version: Preprint
publication: bioRxiv
publication_status: submitted
status: public
title: The splicing paralogues SNRPB and SNRPN control differential metabolic states.
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2026'
...
---
OA_place: repository
OA_type: green
_id: '21962'
abstract:
- lang: eng
text: The generation of faithful cell-type diversity and correct projection neuron
numbers is essential for cerebral cortex development. Corticogenesis is however
susceptible to genetic interference of critical signaling pathways, including
mutations in Mtor/Rptor that lead to microcephaly. How the loss of Rptor/mTORC1
function affects cortical developmental programs, at single cell level, is still
unknown. Here, we utilized Mosaic Analysis with Double Markers (MADM) technology
to probe Rptor gene function upon sparse single cell- or global tissue-wide ablation.
We found that tissue-wide effects drive the etiology of cortical microcephaly
upon loss of Rptor, rather than deficits in projection neuron genesis. Conversely,
Rptor function is cell-autonomously required for postnatal projection neuron survival
in a highly cell-type-specific manner. Collectively, our results suggest that
the fine balance of precise cell-type-specific cell-autonomous Rptor/mTORC1 function
in concert with non-cell-autonomous tissue-wide effects is essential for the development
of a properly-sized cerebral cortex with accurate projection neuron diversity.
acknowledged_ssus:
- _id: PreCl
- _id: LifeSc
- _id: MassSpec
- _id: Bio
acknowledgement: "We thank A. Heger (IST Austria Preclinical Facility), A. Sommer
(VBCF GmbH, NGS Unit), and A.\r\nNicolas (IST Austria Lab Support Facility / Mass
Spectrometry Facility) for technical support; K. Ferencak,\r\nI. Aykara, P. Hirschfeld,
E. Fisher, S. Laukoter, L. Andersen for initial experiments and/or assistance; and\r\nall
members of the Hippenmeyer lab for discussion. This research was supported by the
Scientific Service\r\nUnits (SSU) of IST Austria through resources provided by the
Imaging and Optics- (IOF), Lab Support-\r\n(LSF) and Preclinical Facilities (PCF).
R.B. received support from FWF Meitner-Programm (M 2416). This\r\nwork was also
supported by IST Austria institutional funds; the People Programme (Marie Curie
Actions)\r\nof the European Union’s Seventh Framework Programme (FP7/2007-2013)
under REA grant agreement\r\nNo 618444 to S.H., and the European Research Council
(ERC) under the European Union’s Horizon 2020\r\nresearch and innovation programme
(grant agreement No 725780 LinPro) to S.H."
article_processing_charge: No
author:
- first_name: Ana
full_name: Villalba Requena, Ana
id: 68cb85a0-39f7-11eb-9559-9aaab4f6a247
last_name: Villalba Requena
orcid: 0000-0002-5615-5277
- first_name: Robert J
full_name: Beattie, Robert J
id: 2E26DF60-F248-11E8-B48F-1D18A9856A87
last_name: Beattie
orcid: 0000-0002-8483-8753
- first_name: Florian
full_name: Pauler, Florian
id: 48EA0138-F248-11E8-B48F-1D18A9856A87
last_name: Pauler
orcid: 0000-0002-7462-0048
- first_name: Carmen
full_name: Streicher, Carmen
id: 36BCB99C-F248-11E8-B48F-1D18A9856A87
last_name: Streicher
- first_name: Osvaldo
full_name: Miranda, Osvaldo
id: 862A3C56-A8BF-11E9-B4FA-D9E3E5697425
last_name: Miranda
orcid: 0000-0001-6618-6889
- first_name: Thomas
full_name: Krausgruber, Thomas
last_name: Krausgruber
- first_name: Martin
full_name: Senekowitsch, Martin
last_name: Senekowitsch
- first_name: Matthias
full_name: Farlik, Matthias
last_name: Farlik
- first_name: Christoph
full_name: Bock, Christoph
last_name: Bock
- first_name: Thomas
full_name: Rülicke, Thomas
last_name: Rülicke
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
citation:
ama: Villalba Requena A, Beattie RJ, Pauler F, et al. Mtor/Rptor function globally
prevents cortical microcephaly and cell-autonomously promotes postnatal neuron
survival in cell type specific manner. bioRxiv. doi:10.64898/2026.05.01.722172
apa: Villalba Requena, A., Beattie, R. J., Pauler, F., Streicher, C., Miranda, O.,
Krausgruber, T., … Hippenmeyer, S. (n.d.). Mtor/Rptor function globally prevents
cortical microcephaly and cell-autonomously promotes postnatal neuron survival
in cell type specific manner. bioRxiv. https://doi.org/10.64898/2026.05.01.722172
chicago: Villalba Requena, Ana, Robert J Beattie, Florian Pauler, Carmen Streicher,
Osvaldo Miranda, Thomas Krausgruber, Martin Senekowitsch, et al. “Mtor/Rptor Function
Globally Prevents Cortical Microcephaly and Cell-Autonomously Promotes Postnatal
Neuron Survival in Cell Type Specific Manner.” BioRxiv, n.d. https://doi.org/10.64898/2026.05.01.722172.
ieee: A. Villalba Requena et al., “Mtor/Rptor function globally prevents
cortical microcephaly and cell-autonomously promotes postnatal neuron survival
in cell type specific manner,” bioRxiv. .
ista: Villalba Requena A, Beattie RJ, Pauler F, Streicher C, Miranda O, Krausgruber
T, Senekowitsch M, Farlik M, Bock C, Rülicke T, Hippenmeyer S. Mtor/Rptor function
globally prevents cortical microcephaly and cell-autonomously promotes postnatal
neuron survival in cell type specific manner. bioRxiv, 10.64898/2026.05.01.722172.
mla: Villalba Requena, Ana, et al. “Mtor/Rptor Function Globally Prevents Cortical
Microcephaly and Cell-Autonomously Promotes Postnatal Neuron Survival in Cell
Type Specific Manner.” BioRxiv, doi:10.64898/2026.05.01.722172.
short: A. Villalba Requena, R.J. Beattie, F. Pauler, C. Streicher, O. Miranda, T.
Krausgruber, M. Senekowitsch, M. Farlik, C. Bock, T. Rülicke, S. Hippenmeyer,
BioRxiv (n.d.).
date_created: 2026-06-09T08:08:18Z
date_published: 2026-05-05T00:00:00Z
date_updated: 2026-06-16T08:45:25Z
day: '05'
ddc:
- '570'
department:
- _id: SiHi
doi: 10.64898/2026.05.01.722172
ec_funded: 1
fulldoi: https://doi.org/10.64898/2026.05.01.722172
has_accepted_license: '1'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.64898/2026.05.01.722172
month: '05'
oa: 1
oa_version: Preprint
project:
- _id: 264E56E2-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: M02416
name: Molecular Mechanisms Regulating Gliogenesis in the Neocortex
- _id: 25D61E48-B435-11E9-9278-68D0E5697425
call_identifier: FP7
grant_number: '618444'
name: Molecular Mechanisms of Cerebral Cortex Development
- _id: 260018B0-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '725780'
name: Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development
publication: bioRxiv
publication_status: submitted
status: public
title: Mtor/Rptor function globally prevents cortical microcephaly and cell-autonomously
promotes postnatal neuron survival in cell type specific manner
tmp:
image: /images/cc_by_nc.png
legal_code_url: https://creativecommons.org/licenses/by-nc/4.0/legalcode
name: Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
short: CC BY-NC (4.0)
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2026'
...
---
OA_place: repository
OA_type: green
_id: '21963'
abstract:
- lang: eng
text: The cerebral cortex consists of immense numbers of neuronal and glial cell-types
derived from radial glial progenitor (RGP) cells. How RGPs generate appropriate
quantities of distinct cortical cell-types to safeguard a brain of correct size,
is not well understood. However, genetic aberration in human, including mutations
in PTEN, lead to cortical malformation such as macrocephaly, albeit with unknown
etiology. Here we utilized Mosaic Analysis with Double Markers (MADM)-based clonal
analysis and single cell phenotyping to decipher the role of Pten in neurogenic
and gliogenic RGP lineage progression during cortical ontogeny. While neurogenic
RGP lineage progression and projection neuron production was moderately altered
in the absence of Pten, cortical astrocyte production was drastically increased.
Through genetic epistasis experiments we show that the loss of Pten uncouples
astrocyte generation from essential growth factor signaling hubs, funneling into
MAPK. Collectively, our results suggest that Pten regulates RGP lineage progression
with distinct sequential functions in cortical projection neurogenesis and astrocyte
production to ensure the emergence of a correctly-sized cerebral cortex.
acknowledged_ssus:
- _id: Bio
- _id: LifeSc
- _id: PreCl
acknowledgement: "We thank Kay-Uwe Wagner (Wayne State University) for generously
sharing Jak1/2–flox mouse lines; A.\r\nSommer (VBCF GmbH, NGS Unit) for technical
support; N. Kim, V. Mick, S. Schnabl, S. Gobeil, and L.\r\nAndersen for technical
assistance; all members of the Hippenmeyer lab for discussion and B. Novitch for\r\ncomments
on earlier versions of the manuscript. This research was supported by the Scientific
Service Units\r\n(SSU) of IST Austria through resources provided by the Imaging
and Optics Facility (IOF), Lab Support-\r\n(LSF) and Preclinical Facilities (PCF).
O.A.M received support from the Austrian Academy of Sciences\r\nÖAW (DOC 186584),
and N.A. from FWF Elise Richter Program (Grant V1041T). This work was also\r\nsupported
by IST Austria institutional funds; FWF SFB F78 (Neuro Stem Modulation) to S.H.,
and the\r\nEuropean Research Council (ERC) under the European Union’s Horizon 2020
research and innovation\r\nprogramme (grant agreement No 725780 LinPro) to S.H."
article_processing_charge: No
author:
- first_name: Osvaldo
full_name: Miranda, Osvaldo
id: 862A3C56-A8BF-11E9-B4FA-D9E3E5697425
last_name: Miranda
orcid: 0000-0001-6618-6889
- first_name: Ximena
full_name: Contreras, Ximena
id: 475990FE-F248-11E8-B48F-1D18A9856A87
last_name: Contreras
- first_name: Florian
full_name: Pauler, Florian
id: 48EA0138-F248-11E8-B48F-1D18A9856A87
last_name: Pauler
orcid: 0000-0002-7462-0048
- first_name: Amarbayasgalan
full_name: Davaatseren, Amarbayasgalan
id: 70ADC922-B424-11E9-99E3-BA18E6697425
last_name: Davaatseren
- first_name: Nicole
full_name: Amberg, Nicole
id: 4CD6AAC6-F248-11E8-B48F-1D18A9856A87
last_name: Amberg
orcid: 0000-0002-3183-8207
- first_name: Carmen
full_name: Streicher, Carmen
id: 36BCB99C-F248-11E8-B48F-1D18A9856A87
last_name: Streicher
- first_name: Ana
full_name: Villalba Requena, Ana
id: 68cb85a0-39f7-11eb-9559-9aaab4f6a247
last_name: Villalba Requena
orcid: 0000-0002-5615-5277
- first_name: Anna-Magdalena
full_name: Heger, Anna-Magdalena
id: 4B76FFD2-F248-11E8-B48F-1D18A9856A87
last_name: Heger
- first_name: Corentine
full_name: Marie, Corentine
last_name: Marie
- first_name: Bassem A.
full_name: Hassan, Bassem A.
last_name: Hassan
- first_name: Thomas
full_name: Rülicke, Thomas
last_name: Rülicke
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
citation:
ama: Miranda O, Contreras X, Pauler F, et al. Pten orchestrates neurogenic radial
glia lineage progression and tunes neocortical astrocyte production. bioRxiv.
doi:10.64898/2026.05.01.722191
apa: Miranda, O., Contreras, X., Pauler, F., Davaatseren, A., Amberg, N., Streicher,
C., … Hippenmeyer, S. (n.d.). Pten orchestrates neurogenic radial glia lineage
progression and tunes neocortical astrocyte production. bioRxiv. https://doi.org/10.64898/2026.05.01.722191
chicago: Miranda, Osvaldo, Ximena Contreras, Florian Pauler, Amarbayasgalan Davaatseren,
Nicole Amberg, Carmen Streicher, Ana Villalba Requena, et al. “Pten Orchestrates
Neurogenic Radial Glia Lineage Progression and Tunes Neocortical Astrocyte Production.”
BioRxiv, n.d. https://doi.org/10.64898/2026.05.01.722191.
ieee: O. Miranda et al., “Pten orchestrates neurogenic radial glia lineage
progression and tunes neocortical astrocyte production,” bioRxiv. .
ista: Miranda O, Contreras X, Pauler F, Davaatseren A, Amberg N, Streicher C, Villalba
Requena A, Heger A-M, Marie C, Hassan BA, Rülicke T, Hippenmeyer S. Pten orchestrates
neurogenic radial glia lineage progression and tunes neocortical astrocyte production.
bioRxiv, 10.64898/2026.05.01.722191.
mla: Miranda, Osvaldo, et al. “Pten Orchestrates Neurogenic Radial Glia Lineage
Progression and Tunes Neocortical Astrocyte Production.” BioRxiv, doi:10.64898/2026.05.01.722191.
short: O. Miranda, X. Contreras, F. Pauler, A. Davaatseren, N. Amberg, C. Streicher,
A. Villalba Requena, A.-M. Heger, C. Marie, B.A. Hassan, T. Rülicke, S. Hippenmeyer,
BioRxiv (n.d.).
corr_author: '1'
date_created: 2026-06-09T08:08:53Z
date_published: 2026-05-05T00:00:00Z
date_updated: 2026-06-16T08:57:20Z
day: '05'
ddc:
- '570'
department:
- _id: SiHi
- _id: PreCl
- _id: GradSch
doi: 10.64898/2026.05.01.722191
ec_funded: 1
fulldoi: https://doi.org/10.64898/2026.05.01.722191
has_accepted_license: '1'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.64898/2026.05.01.722191
month: '05'
oa: 1
oa_version: Preprint
project:
- _id: 059F6AB4-7A3F-11EA-A408-12923DDC885E
grant_number: F7805
name: Stem Cell Modulation in Neural Development and Regeneration/ P05-Molecular
Mechanisms of Neural Stem Cell Lineage Progression
- _id: 260018B0-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '725780'
name: Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development
publication: bioRxiv
publication_status: submitted
status: public
title: Pten orchestrates neurogenic radial glia lineage progression and tunes neocortical
astrocyte production
tmp:
image: /images/cc_by_nc.png
legal_code_url: https://creativecommons.org/licenses/by-nc/4.0/legalcode
name: Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
short: CC BY-NC (4.0)
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2026'
...
---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
PlanS_conform: '1'
_id: '22714'
abstract:
- lang: eng
text: Radial glial progenitors (RGPs) generate all projection neurons (PNs) in the
cerebral cortex through incompletely understood processes. We combined Mosaic
Analysis with Double Markers at embryonic stages (E)12.5 and E13.5 with early
postnatal callosal tracing to dissect RGP lineage progression. We find that multipotent
RGPs generate all extra-telencephalic (ET) and intra-telencephalic (IT) PNs via
parallel sublineages that emerge simultaneously at neurogenesis onset. ET-PN production
progresses exclusively via small, self-consuming lineages; IT-PN lineages feature
RGPs generating large translaminar outputs. The early emergence of IT-PN–fated
RGPs, coinciding with a switch to direct neurogenesis, contributes to the stereotyped
population-level progression of the multipotent lineage. We also identify POU3F
transcription factors as candidate regulators of IT-PN fate via noncanonical mitotic
chromatin binding. The results support a model whereby IT- and ET-PNs arise from
an early bifurcation and parallel specification within the multipotent RGP lineage.
acknowledgement: 'We thank M. caouyette for the plasmid construction for Pou3f1overexpression;
d. Pinto-Benito for valuable assistance with shRnA validation in n2A cells andqPcR
experiments; c. Varela-Martínez for help with the code for graphical analysis; allmembers
from the nieto’s lab for comment on the manuscript, specially to F. Martín for theinsightful
discussions; J. c. Oliveros and J. A. García from the computational service of the
cnBfor help with the analysis of RnAseq dataset; c. O. Sorzano for help with statistical
analysis; andA. Oña and the service of Advance Optical Microscopy of the cnB for
technical advice.Funding: i.V.-M. holds a fellowship funded by MciciU (PRe-2018-083376)
and 2023 eMBOscientific exchange grant 10214. the work was funded by grants to M.n.
(Pid2020-112831GB- i00 and Pid2023-146322nB- i00 by Mcin/Aei/10.13039/501100011033
and by“eRdF A way of making europe”).'
article_processing_charge: Yes
article_type: original
author:
- first_name: Irene
full_name: Varela Martínez, Irene
id: a69b5985-8829-11f0-8fc2-d0af58f64471
last_name: Varela Martínez
- first_name: Ana
full_name: Villalba Requena, Ana
id: 68cb85a0-39f7-11eb-9559-9aaab4f6a247
last_name: Villalba Requena
orcid: 0000-0002-5615-5277
- first_name: Jorge
full_name: García-Marqués, Jorge
last_name: García-Marqués
- first_name: Alfonso
full_name: Aguilera, Alfonso
last_name: Aguilera
- first_name: Diogo S.
full_name: Castro, Diogo S.
last_name: Castro
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
- first_name: Marta
full_name: Nieto, Marta
last_name: Nieto
citation:
ama: Varela Martínez I, Villalba Requena A, García-Marqués J, et al. Early fate
diversification of radial glial progenitors during corticogenesis. Science
Advances. 2026;12(32):eadw5487. doi:10.1126/sciadv.adw5487
apa: Varela Martínez, I., Villalba Requena, A., García-Marqués, J., Aguilera, A.,
Castro, D. S., Hippenmeyer, S., & Nieto, M. (2026). Early fate diversification
of radial glial progenitors during corticogenesis. Science Advances. AAAS.
https://doi.org/10.1126/sciadv.adw5487
chicago: Varela Martínez, Irene, Ana Villalba Requena, Jorge García-Marqués, Alfonso
Aguilera, Diogo S. Castro, Simon Hippenmeyer, and Marta Nieto. “Early Fate Diversification
of Radial Glial Progenitors during Corticogenesis.” Science Advances. AAAS,
2026. https://doi.org/10.1126/sciadv.adw5487.
ieee: I. Varela Martínez et al., “Early fate diversification of radial glial
progenitors during corticogenesis,” Science Advances, vol. 12, no. 32.
AAAS, p. eadw5487, 2026.
ista: Varela Martínez I, Villalba Requena A, García-Marqués J, Aguilera A, Castro
DS, Hippenmeyer S, Nieto M. 2026. Early fate diversification of radial glial progenitors
during corticogenesis. Science Advances. 12(32), eadw5487.
mla: Varela Martínez, Irene, et al. “Early Fate Diversification of Radial Glial
Progenitors during Corticogenesis.” Science Advances, vol. 12, no. 32,
AAAS, 2026, p. eadw5487, doi:10.1126/sciadv.adw5487.
short: I. Varela Martínez, A. Villalba Requena, J. García-Marqués, A. Aguilera,
D.S. Castro, S. Hippenmeyer, M. Nieto, Science Advances 12 (2026) eadw5487.
das_tickbox: '1'
dataavailabilitystatement: 'All data and code needed to evaluate and reproduce the
results in the paper are present in the paper and/or the Supplementary Materials.
Source data underlying all figures (including the clonal atlas) are provided in
the Supplementary Materials. RnA-seq analysis code has been deposited in Zenodo
(dOi: 10.5281/zenodo.14609057). this study did not generate new materials.'
date_created: 2026-08-16T22:01:43Z
date_published: 2026-08-07T00:00:00Z
date_updated: 2026-08-20T05:45:28Z
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doi: 10.1126/sciadv.adw5487
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publication_identifier:
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supplementarymaterial: yes
title: Early fate diversification of radial glial progenitors during corticogenesis
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 12
year: '2026'
...
---
OA_place: publisher
OA_type: hybrid
PlanS_conform: '1'
_id: '19718'
abstract:
- lang: eng
text: The cerebral cortex is arguably the most complex organ in humans. The cortical
architecture is characterized by a remarkable diversity of neuronal and glial
cell types that make up its neuronal circuits. Following a precise temporally
ordered program, radial glia progenitor (RGP) cells generate all cortical excitatory
projection neurons and glial cell-types. Cortical excitatory projection neurons
are produced either directly or via intermediate progenitors, through indirect
neurogenesis. How the extensive cortical cell-type diversity is generated during
cortex development remains, however, a fundamental open question. How do RGPs
quantitatively and qualitatively generate all the neocortical neurons? How does
direct and indirect neurogenesis contribute to the establishment of neuronal and
lineage heterogeneity? Whether RGPs represent a homogeneous and/or multipotent
progenitor population, or if RGPs consist of heterogeneous groups is currently
also not known. In this review, we will summarize the latest findings that contributed
to a deeper insight into the above key questions.
acknowledgement: We wish to thank all members of the Hippenmeyer laboratory at ISTA
for exciting discussions on the subject of this review. We apologize to colleagues
whose work we could not cite and/or discuss in the frame of the available space.
Work in the Hippenmeyer laboratory on the discussed topic is supported by ISTA institutional
funds, an EMBO LTF (ALTF 994–2023) to F.P, and FWF SFB F78 to S.H.
article_number: '103046'
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Fabrizia
full_name: Pipicelli, Fabrizia
id: 649134fd-d012-11ed-8f82-db1e5050f9ba
last_name: Pipicelli
- first_name: Ana
full_name: Villalba Requena, Ana
id: 68cb85a0-39f7-11eb-9559-9aaab4f6a247
last_name: Villalba Requena
orcid: 0000-0002-5615-5277
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
citation:
ama: Pipicelli F, Villalba Requena A, Hippenmeyer S. How radial glia progenitor
lineages generate cell-type diversity in the developing cerebral cortex. Current
Opinion in Neurobiology. 2025;93. doi:10.1016/j.conb.2025.103046
apa: Pipicelli, F., Villalba Requena, A., & Hippenmeyer, S. (2025). How radial
glia progenitor lineages generate cell-type diversity in the developing cerebral
cortex. Current Opinion in Neurobiology. Elsevier. https://doi.org/10.1016/j.conb.2025.103046
chicago: Pipicelli, Fabrizia, Ana Villalba Requena, and Simon Hippenmeyer. “How
Radial Glia Progenitor Lineages Generate Cell-Type Diversity in the Developing
Cerebral Cortex.” Current Opinion in Neurobiology. Elsevier, 2025. https://doi.org/10.1016/j.conb.2025.103046.
ieee: F. Pipicelli, A. Villalba Requena, and S. Hippenmeyer, “How radial glia progenitor
lineages generate cell-type diversity in the developing cerebral cortex,” Current
Opinion in Neurobiology, vol. 93. Elsevier, 2025.
ista: Pipicelli F, Villalba Requena A, Hippenmeyer S. 2025. How radial glia progenitor
lineages generate cell-type diversity in the developing cerebral cortex. Current
Opinion in Neurobiology. 93, 103046.
mla: Pipicelli, Fabrizia, et al. “How Radial Glia Progenitor Lineages Generate Cell-Type
Diversity in the Developing Cerebral Cortex.” Current Opinion in Neurobiology,
vol. 93, 103046, Elsevier, 2025, doi:10.1016/j.conb.2025.103046.
short: F. Pipicelli, A. Villalba Requena, S. Hippenmeyer, Current Opinion in Neurobiology
93 (2025).
corr_author: '1'
date_created: 2025-05-20T10:20:09Z
date_published: 2025-08-01T00:00:00Z
date_updated: 2025-12-30T10:54:14Z
day: '01'
ddc:
- '570'
department:
- _id: SiHi
doi: 10.1016/j.conb.2025.103046
external_id:
isi:
- '001496227000001'
pmid:
- '40383049'
file:
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content_type: application/pdf
creator: dernst
date_created: 2025-12-30T08:25:49Z
date_updated: 2025-12-30T08:25:49Z
file_id: '20894'
file_name: 2025_CurrentOpNeurobiology_Pipicelli.pdf
file_size: 1592649
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success: 1
file_date_updated: 2025-12-30T08:25:49Z
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intvolume: ' 93'
isi: 1
language:
- iso: eng
month: '08'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 059F6AB4-7A3F-11EA-A408-12923DDC885E
grant_number: F7805
name: Stem Cell Modulation in Neural Development and Regeneration/ P05-Molecular
Mechanisms of Neural Stem Cell Lineage Progression
- _id: 7c084566-9f16-11ee-852c-c88a1dbbf1cf
grant_number: ALTF 994-2023
name: Role of cell lineage in generating cell-type diversity in developing neocortex’
publication: Current Opinion in Neurobiology
publication_identifier:
issn:
- 0959-4388
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: How radial glia progenitor lineages generate cell-type diversity in the developing
cerebral cortex
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 93
year: '2025'
...
---
OA_place: repository
OA_type: green
_id: '19717'
abstract:
- lang: eng
text: Radial glial progenitors (RGPs) generate all projection neurons (PNs) in the
cerebral cortex through incompletely understood processes. Herein, we combine
Mosaic Analysis with Double Markers (MADM)-based clonal analysis at embryonic
days 12.5 and 13.5 with early postnatal callosal tracing to reveal a lineage progression
that challenges the inside-outside model of cortical development and the conventional
view of an invariable sequence of asymmetric neurogenic divisions. Our data demonstrate
that early multipotent RGPs generate all extra-telencephalic (ET) and intra-telencephalic
(IT) PNs across all layers through parallel sublineages and the random specification,
during the earliest neurogenic divisions, of fate-restricted daughter RGPs. While
the neuronal production of the parental multipotent RGPs consists of small ET-PN
or IT-PN outputs, fate-restricted RGPs produce larger translaminar outputs spanning
deep and upper layers of only IT-PNs, the predominant mammalian PN subtype. We
further show that the emergence of IT-PN fate-restricted RGPs also leads to quantitatively
and temporally stereotyped neurogenesis population-wise.
acknowledgement: "We thank M. Caouyette for the plasmid construction for Pou3f1 overexpression;
C. Varela747 Martínez for help with the code for graphical analysis; all members
from the Nieto’s lab for\r\ncomment on the manuscript, specially to F. Martín for
the insightful discussions;J.C. Oliveros\r\nand J.A. García from the computational
service of the CNB for help with the analysis of\r\nRNAseq dataset, C.O. Sorzano
for the help with statistical analysis, and the service of\r\nAdvance Optical Microscopy
of the CNB for their technical advice.\r\nI.V.M holds a fellowship funded by MCICIU
(PRE-2018-083376), the work was funded by\r\nPID2020-112831GB-I00 funded by MCIN/AEI
/10.13039/501100011033.\r\n"
article_processing_charge: No
author:
- first_name: I
full_name: Varela-Martínez, I
last_name: Varela-Martínez
- first_name: Ana
full_name: Villalba Requena, Ana
id: 68cb85a0-39f7-11eb-9559-9aaab4f6a247
last_name: Villalba Requena
orcid: 0000-0002-5615-5277
- first_name: J.
full_name: Garcia-Marqués, J.
last_name: Garcia-Marqués
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
- first_name: M.
full_name: Nieto, M.
last_name: Nieto
citation:
ama: Varela-Martínez I, Villalba Requena A, Garcia-Marqués J, Hippenmeyer S, Nieto
M. Early emergence of projection-subtype fate-restricted radial glial progenitors
orchestrates neocortical neurogenesis. bioRxiv. doi:10.1101/2025.05.07.652665
apa: Varela-Martínez, I., Villalba Requena, A., Garcia-Marqués, J., Hippenmeyer,
S., & Nieto, M. (n.d.). Early emergence of projection-subtype fate-restricted
radial glial progenitors orchestrates neocortical neurogenesis. bioRxiv.
https://doi.org/10.1101/2025.05.07.652665
chicago: Varela-Martínez, I, Ana Villalba Requena, J. Garcia-Marqués, Simon Hippenmeyer,
and M. Nieto. “Early Emergence of Projection-Subtype Fate-Restricted Radial Glial
Progenitors Orchestrates Neocortical Neurogenesis.” BioRxiv, n.d. https://doi.org/10.1101/2025.05.07.652665.
ieee: I. Varela-Martínez, A. Villalba Requena, J. Garcia-Marqués, S. Hippenmeyer,
and M. Nieto, “Early emergence of projection-subtype fate-restricted radial glial
progenitors orchestrates neocortical neurogenesis,” bioRxiv. .
ista: Varela-Martínez I, Villalba Requena A, Garcia-Marqués J, Hippenmeyer S, Nieto
M. Early emergence of projection-subtype fate-restricted radial glial progenitors
orchestrates neocortical neurogenesis. bioRxiv, 10.1101/2025.05.07.652665.
mla: Varela-Martínez, I., et al. “Early Emergence of Projection-Subtype Fate-Restricted
Radial Glial Progenitors Orchestrates Neocortical Neurogenesis.” BioRxiv,
doi:10.1101/2025.05.07.652665.
short: I. Varela-Martínez, A. Villalba Requena, J. Garcia-Marqués, S. Hippenmeyer,
M. Nieto, BioRxiv (n.d.).
date_created: 2025-05-20T10:19:29Z
date_published: 2025-05-07T00:00:00Z
date_updated: 2026-08-13T07:16:48Z
day: '07'
department:
- _id: SiHi
doi: 10.1101/2025.05.07.652665
fulldoi: https://doi.org/10.1101/2025.05.07.652665
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1101/2025.05.07.652665
month: '05'
oa: 1
oa_version: Preprint
publication: bioRxiv
publication_status: submitted
status: public
title: Early emergence of projection-subtype fate-restricted radial glial progenitors
orchestrates neocortical neurogenesis
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2025'
...
---
OA_place: publisher
OA_type: free access
_id: '12542'
abstract:
- lang: eng
text: In this issue of Neuron, Espinosa-Medina et al.1 present the TEMPO (Temporal
Encoding and Manipulation in a Predefined Order) system, which enables the marking
and genetic manipulation of sequentially generated cell lineages in vertebrate
species in vivo.
article_processing_charge: No
article_type: letter_note
author:
- first_name: Ana
full_name: Villalba Requena, Ana
id: 68cb85a0-39f7-11eb-9559-9aaab4f6a247
last_name: Villalba Requena
orcid: 0000-0002-5615-5277
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
citation:
ama: Villalba Requena A, Hippenmeyer S. Going back in time with TEMPO. Neuron.
2023;111(3):291-293. doi:10.1016/j.neuron.2023.01.006
apa: Villalba Requena, A., & Hippenmeyer, S. (2023). Going back in time with
TEMPO. Neuron. Elsevier. https://doi.org/10.1016/j.neuron.2023.01.006
chicago: Villalba Requena, Ana, and Simon Hippenmeyer. “Going Back in Time with
TEMPO.” Neuron. Elsevier, 2023. https://doi.org/10.1016/j.neuron.2023.01.006.
ieee: A. Villalba Requena and S. Hippenmeyer, “Going back in time with TEMPO,” Neuron,
vol. 111, no. 3. Elsevier, pp. 291–293, 2023.
ista: Villalba Requena A, Hippenmeyer S. 2023. Going back in time with TEMPO. Neuron.
111(3), 291–293.
mla: Villalba Requena, Ana, and Simon Hippenmeyer. “Going Back in Time with TEMPO.”
Neuron, vol. 111, no. 3, Elsevier, 2023, pp. 291–93, doi:10.1016/j.neuron.2023.01.006.
short: A. Villalba Requena, S. Hippenmeyer, Neuron 111 (2023) 291–293.
corr_author: '1'
date_created: 2023-02-12T23:00:58Z
date_published: 2023-02-01T00:00:00Z
date_updated: 2026-06-18T17:27:44Z
day: '01'
ddc:
- '570'
department:
- _id: SiHi
doi: 10.1016/j.neuron.2023.01.006
external_id:
isi:
- '000994473300001'
pmid:
- '36731425'
fulldoi: https://doi.org/10.1016/j.neuron.2023.01.006
intvolume: ' 111'
isi: 1
issue: '3'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1016/j.neuron.2023.01.006
month: '02'
oa: 1
oa_version: Published Version
page: 291-293
pmid: 1
publication: Neuron
publication_identifier:
eissn:
- 1097-4199
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: Going back in time with TEMPO
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 111
year: '2023'
...
---
_id: '14757'
abstract:
- lang: eng
text: The cerebral cortex is comprised of a vast cell-type diversity sequentially
generated by cortical progenitor cells. Faithful progenitor lineage progression
requires the tight orchestration of distinct molecular and cellular mechanisms
regulating proper progenitor proliferation behavior and differentiation. Correct
execution of developmental programs involves a complex interplay of cell intrinsic
and tissue-wide mechanisms. Many studies over the past decades have been able
to determine a plethora of genes critically involved in cortical development.
However, only a few made use of genetic paradigms with sparse and global gene
deletion to probe cell-autonomous vs. tissue-wide contribution. In this chapter,
we will elaborate on the importance of dissecting the cell-autonomous and tissue-wide
mechanisms to gain a precise understanding of gene function during radial glial
progenitor lineage progression.
article_processing_charge: No
author:
- first_name: Ana
full_name: Villalba Requena, Ana
id: 68cb85a0-39f7-11eb-9559-9aaab4f6a247
last_name: Villalba Requena
orcid: 0000-0002-5615-5277
- first_name: Nicole
full_name: Amberg, Nicole
id: 4CD6AAC6-F248-11E8-B48F-1D18A9856A87
last_name: Amberg
orcid: 0000-0002-3183-8207
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
citation:
ama: 'Villalba Requena A, Amberg N, Hippenmeyer S. Interplay of Cell‐autonomous
Gene Function and Tissue‐wide Mechanisms Regulating Radial Glial Progenitor Lineage
Progression. In: Huttner W, ed. Neocortical Neurogenesis in Development and
Evolution. Wiley; 2023:169-191. doi:10.1002/9781119860914.ch10'
apa: Villalba Requena, A., Amberg, N., & Hippenmeyer, S. (2023). Interplay of
Cell‐autonomous Gene Function and Tissue‐wide Mechanisms Regulating Radial Glial
Progenitor Lineage Progression. In W. Huttner (Ed.), Neocortical Neurogenesis
in Development and Evolution (pp. 169–191). Wiley. https://doi.org/10.1002/9781119860914.ch10
chicago: Villalba Requena, Ana, Nicole Amberg, and Simon Hippenmeyer. “Interplay
of Cell‐autonomous Gene Function and Tissue‐wide Mechanisms Regulating Radial
Glial Progenitor Lineage Progression.” In Neocortical Neurogenesis in Development
and Evolution, edited by Wieland Huttner, 169–91. Wiley, 2023. https://doi.org/10.1002/9781119860914.ch10.
ieee: A. Villalba Requena, N. Amberg, and S. Hippenmeyer, “Interplay of Cell‐autonomous
Gene Function and Tissue‐wide Mechanisms Regulating Radial Glial Progenitor Lineage
Progression,” in Neocortical Neurogenesis in Development and Evolution,
W. Huttner, Ed. Wiley, 2023, pp. 169–191.
ista: 'Villalba Requena A, Amberg N, Hippenmeyer S. 2023.Interplay of Cell‐autonomous
Gene Function and Tissue‐wide Mechanisms Regulating Radial Glial Progenitor Lineage
Progression. In: Neocortical Neurogenesis in Development and Evolution. , 169–191.'
mla: Villalba Requena, Ana, et al. “Interplay of Cell‐autonomous Gene Function and
Tissue‐wide Mechanisms Regulating Radial Glial Progenitor Lineage Progression.”
Neocortical Neurogenesis in Development and Evolution, edited by Wieland
Huttner, Wiley, 2023, pp. 169–91, doi:10.1002/9781119860914.ch10.
short: A. Villalba Requena, N. Amberg, S. Hippenmeyer, in:, W. Huttner (Ed.), Neocortical
Neurogenesis in Development and Evolution, Wiley, 2023, pp. 169–191.
corr_author: '1'
date_created: 2024-01-08T13:16:36Z
date_published: 2023-08-08T00:00:00Z
date_updated: 2024-10-09T21:07:46Z
day: '08'
department:
- _id: SiHi
doi: 10.1002/9781119860914.ch10
editor:
- first_name: Wieland
full_name: Huttner, Wieland
last_name: Huttner
fulldoi: https://doi.org/10.1002/9781119860914.ch10
language:
- iso: eng
month: '08'
oa_version: None
page: 169-191
publication: Neocortical Neurogenesis in Development and Evolution
publication_identifier:
eisbn:
- '9781119860914'
publication_status: published
publisher: Wiley
quality_controlled: '1'
scopus_import: '1'
status: public
title: Interplay of Cell‐autonomous Gene Function and Tissue‐wide Mechanisms Regulating
Radial Glial Progenitor Lineage Progression
type: book_chapter
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2023'
...