SCIENCE science.orgganoid models and studies of patient tissue
advance, critical questions will be whether
other TSC-associated tumors have CLIP cell–
like features, including low amounts of TSC
protein, and whether second hits in the TSC
genes are required for initiation.
It remains unknown what targetable fea-
tures are distinct to CLIP cells. Although
epidermal growth factor receptor (EGFR) is
expressed in CLIP cells, and Eichmüller et
al. find that EGFR inhibition blocks lesion
outgrowth in organoids, other progenitor
populations in the brain also dynamically
express EGFR but appear less susceptible to
the effects of TSC2 mutation ( 11 ). The relative
prevalence of subcortical tumors in patients
raises an additional question: If the CLIP-like
state in TSC2-heterozygous cells is sufficient
to induce formation of all brain hamartomas,
why do many TSC patients develop SENs
but a minority suffer from the larger SEGA
tumors? Immune infiltration, which is not
yet captured in TSC organoid studies, may
be an important modulator of this and other
manifestations ( 12 ). Further development
of organoid models has the potential to ap-
proach these questions to better understand
TSC and other rare disorders ( 13 , 14 ).
It will be essential to determine how the
cell types described by Eichmüller et al. align
with recent single-cell studies of human de-
velopment. In particular, emerging data from
cellular barcoding and lineage tracing suggest
that neuronal lineages previously thought to
be generated in separate subregions of the
developing brain by either cortical progeni-
tors or caudal ganglionic eminence progeni-
tors, which produce CLIP cells, can both
emerge from single cortical progenitor cells
( 15 ). If a CLIP-like state emerges in parallel
in multiple lineages during development,
this would again change our understanding
of where and how TSC tumors arise. j
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ACKNOWLEDGMENTS
The au thors thank S. Bagwe for assistance.
10.1126/science.abn6158NEUROSCIENCEHuman cortical interneuron
development unraveled
By Nicoletta KessarisT
he cerebral cortex is the most en-
larged component of the human
brain. It is the seat for higher-order
brain functions and the biggest in-
formation processing center of the
human brain. Interneurons, one of
two major classes of neurons in the cortex,
have expanded in number in proportion
to cortical volume, but their diversity—the
number of different subtypes—remains
comparable to that of rodents. Shi et al. ( 1 )
reported conservation of the genetic net-
works that instruct interneuron identities
between human and mouse, explaining
how the same set of interneuron subtypes
arises across species. On page 402 of this
issue, Paredes et al. ( 2 ) find a distinctive
cellular organization of the embryonic
brain area where cortical interneurons are
born and an extended period of neurogen-
esis in humans compared with rodents,
explaining how interneuron numbers have
increased. These studies aid our under-
standing of human cortical interneuron
development and provide a framework for
studying human disease.
Improvements in single-cell isolation
techniques, large-scale gene expression
technologies, and data analysis tools have
enabled the characterization and compari-
son of individual neurons from different
species. Between 40 and 60 different sub-
types of interneurons have been identified
in the adult mouse cortex ( 3 ), and homo-
logs of these have been detected in hu-
mans, with variation in abundance, distri-
bution, gene expression, and morphology
( 4 , 5 ). What is the importance of this diver-
sity? Distinct functions have been identi-
fied for some of the most abundant pop-
ulations, but the roles of all the different
interneuron populations in cortical func-
tion and animal behavior are far from un-
derstood. Progress has been hampered by
our failure, until recently, to comprehend
the full extent of interneuron diversity andour inability to identify different subtypes
in live behaving animals. As genetic tools
and technologies for detecting and imag-
ing single neurons and their activities in
intact brains improve, so will our insight
into the function of interneuron diversity.
The origin of cortical interneurons in
the embryonic brain has been extensively
studied in mice. Two major sources have
been identified in the subcortical brain:
the medial and caudal ganglionic emi-
nences (MGE and CGE) ( 6 ). Both are found
in human embryonic brains, and imma-
ture cortical interneurons have been seen
migrating out toward the developing cor-
tex in slice cultures ( 7 , 8 ). How 40 to 60
different types of cortical interneurons
arise from two pools of neural stem cells
in the embryo remains unknown. Major
regulators of gene expression have been
identified in neural stem cells and imma-
ture cortical interneurons in rodents, but
so far, these are insufficient to explain
the complexity of the cortical interneuron
population ( 9 , 10 ). The concept of “nature
versus nurture” has been invoked: Could
some diversity be imposed after cortical
interneurons enter the cortex and settle at
their final destinations?
To decipher the extent to which inter-
neuron characteristics are determined at
the source and to identify genetic pathways
that generate diversity, transcriptomic anal-
yses have been performed on single cells
isolated from mouse ( 11 , 12 ) and human ( 1 ,
13 ) embryonic ganglionic eminences. This
involved the isolation of neuronal progeni-
tors—neural stem cells—and young neurons
from the embryonic brain and the charac-
terization of gene expression in each cell.
All four studies demonstrated that imma-
ture, but genetically discernible, cortical in-
terneuron subtypes can be identified soon
after they are generated in the ganglionic
eminences and before they enter the cortex.
This argues against major identity charac-
teristics acquired de novo when these cells
reach their destination. These findings also
suggest that the transcriptomic signatures
that interneurons exhibit upon maturation
are largely defined at the source when these
cells are born, through genetic programsWolfson Institute for Biomedical Research and Department of
Cell and Developmental Biology, University College London,
Gower Street, London, UK. Email: [email protected]New understanding of principles of neurogenesis
widens the use of preclinical models
28 JANUARY 2022 • VOL 375 ISSUE 6579 383