Selective Depletion of Molecularly Defined Cortical Interneurons in Human Holoprosencephaly with Severe Striatal Hypoplasia
Open accessAbstract
Cortical excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons follow substantially different developmental programs. In rodents, projection neurons originate from progenitors within the dorsal forebrain, whereas interneurons arise from progenitors in the ventral forebrain. In contrast, it has been proposed that in humans, the majority of cortical interneurons arise from progenitors within the dorsal forebrain, suggesting that their origin and migration is complex and evolutionarily divergent. However, whether molecularly defined human cortical interneuron subtypes originate from distinct progenitors, including those in the ventral forebrain, remains unknown. Furthermore, abnormalities in cortical interneurons have been linked to human disorders, yet no distinct cell population selective loss has been reported. Here we show that cortical interneurons expressing nitric oxide synthase 1, neuropeptide Y, and somatostatin, are either absent or substantially reduced in fetal and infant cases of human holoprosencephaly (HPE) with severe ventral forebrain hypoplasia. Notably, another interneuron subtype normally abundant from the early fetal period, marked by calretinin expression, and different subtypes of projection neuron were present in the cortex of control and HPE brains. These findings have important implications for the understanding of neuronal pathogenesis underlying the clinical manifestations associated with HPE and the developmental origins of human cortical interneuron diversity.
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Nonhuman primates and humans have distinct populations of GABAergic neurons which originate in proliferative zones of the dorsal telencephalon.
“Furthermore, it appears that nonhuman primates and humans have distinct populations of GABAergic neurons which originate in proliferative zones of the dorsal telencephalon [193, 194].”
From Development of prefrontal cortex (2022) · cites this paper as [194]
The Discussion (page unavailable) reports CALB2-positive interneurons and putative progenitors in dorsal cortical proliferative zones of midfetal humans and cynomolgus monkeys. It suggests that some human interneurons may derive from cortical progenitors, but explicitly says whether those progenitors give rise to interneurons within the proliferative zones remains undetermined; their origin there in both groups is therefore not established. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGABAergic inhibitory interneurons mostly originate from the ganglionic eminences of the ventral telencephalon.
“which recent studies have shown mostly originate from the ganglionic eminences of the ventral telencephalon (i.e., the subpallium) (Fertuzinhos et al., 2009; Hansen et al., 2013; Hansen et al., 2010; Ma et al., 2013).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Fertuzinhos et al., 2009
Human GABAergic interneurons are largely generated ventrally from the ganglionic eminences in the basal ganglia primordia and migrate tangentially into the cortical plate.
“human GABAergic interneurons are largely generated ventrally from the ganglionic eminences in the basal ganglia primordia and migrate tangentially into the CP (Fertuzinhos et al., 2009; Hansen et al., 2013; Hansen et al., 2010; Ma et al., 2013; Radonjic et al., 2014).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Fertuzinhos et al., 2009
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Cites
Interneurons of the neocortical inhibitory system
Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., & Wu, C. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1519 · Cited by 2,954 · see citing works
Neuronal subtype specification in the cerebral cortex
Molyneaux, B. J., Arlotta, P., Menezes, J. R. L., & Macklis, J. D. (2007) · Nature reviews. Neuroscience · doi:10.1038/nrn2151 · Cited by 1,632 · see citing works
Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex
The Petilla Interneuron Nomenclature Group (PING) (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2402 · Cited by 1,491 · see citing works
Interneuron Migration from Basal Forebrain to Neocortex: Dependence on <i>Dlx</i> Genes
Anderson, S. A., Eisenstat, D. D., Shi, L., & Rubenstein, J. L. R. (1997) · Science · doi:10.1126/science.278.5337.474 · Cited by 1,462 · see citing works
The origin and specification of cortical interneurons
Wonders, C. P., & Anderson, S. A. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1954 · Cited by 980 · see citing works
Handbook of Clinical Neurology
Jellinger, K. A. (2008) · European Journal of Neurology · doi:10.1111/j.1468-1331.2008.02422.x · Cited by 755 · see citing works
Origin of GABAergic neurons in the human neocortex
Letinić, K., Zoncu, R., & RAKIC, P. T. (2002) · Nature · doi:10.1038/nature00779 · Cited by 718 · see citing works
Origins of Cortical Interneuron Subtypes
Xu, Q., Cobos, I., De La Cruz, E., Rubenstein, J. L., & Anderson, S. A. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.5667-03.2004 · Cited by 639 · see citing works
GABAergic Neurons and Their Role in Cortical Plasticity in Primates
Jones, E. G. (1993) · Cerebral Cortex · doi:10.1093/cercor/3.5.361-a · Cited by 489 · see citing works
Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain
Ferland, R. J., Cherry, T. J., Preware, P. O., Morrisey, E. E., & Walsh, C. A. (2003) · The Journal of Comparative Neurology · doi:10.1002/cne.10654 · Cited by 477 · see citing works
Kawaguchi, Y., & Kondo, S. (2002) · Journal of Neurocytology · doi:10.1023/a:1024126110356 · Cited by 395 · see citing works
The determination of projection neuron identity in the developing cerebral cortex
Leone, D. P., Srinivasan, K., Chen, B., Alcamo, E., & McConnell, S. K. (2008) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2008.05.006 · Cited by 382 · see citing works
Three distinct subpopulations of GABAergic neurons in rat frontal agranular cortex
Kubota, Y., Hattori, R., & Yui, Y. (1994) · Brain Research · doi:10.1016/0006-8993(94)91060-x · Cited by 365 · see citing works
Pleasure, S. J., Anderson, S. A., Hevner, R. F., Bagri, A., Marín, Ó., Lowenstein, D. H., & Rubenstein, J. L. R. (2000) · Neuron · doi:10.1016/s0896-6273(00)00149-5 · Cited by 356 · see citing works
Transcriptional Regulation of Cortical Neuron Migration by POU Domain Factors
McEvilly, R. J., de Diaz, M. O., Schonemann, M. D., Hooshmand, F., & Rosenfeld, M. G. (2002) · Science · doi:10.1126/science.1067132 · Cited by 271 · see citing works
Kwan, K. Y., Lam, M. M. S., Krsnik, Ž., Kawasawa, Y. I., Lefebvre, V., & Šestan, N. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806791105 · Cited by 271 · see citing works
Self-citationContributions of cortical subventricular zone to the development of the human cerebral cortex
Zecevic, N., Chen, Y., & Filipovic, R. (2005) · The Journal of Comparative Neurology · doi:10.1002/cne.20714 · Cited by 269 · see citing works
Genetics of ventral forebrain development and holoprosencephaly
Muenke, M. (2000) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(00)00084-8 · Cited by 266 · see citing works
Pathoarchitectonic Studies of Cerebral Malformations
Yakovlev, P. I. (1959) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-195901000-00003 · Cited by 259 · see citing works
Chen, J.-G., Rašin, M.-R., Kwan, K. Y., & Šestan, N. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509032102 · Cited by 246 · see citing works
Self-citationThe Cells of Cajal-Retzius: Still a Mystery One Century After
Soriano, E., & del Rı́o, J. A. (2005) · Neuron · doi:10.1016/j.neuron.2005.04.019 · Cited by 237 · see citing works
Mutations in TITF-1 are associated with benign hereditary chorea
Breedveld, G. J. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.8.971 · Cited by 223 · see citing works
Lewis, D. A., & Lund, J. S. (1990) · The Journal of Comparative Neurology · doi:10.1002/cne.902930406 · Cited by 220 · see citing works
Cell and molecular mechanisms involved in the migration of cortical interneurons
Métin, C., Baudoin, J., Rakić, S., & Parnavelas, J. G. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.04630.x · Cited by 216 · see citing works
Gabbott, P. L. A., & Bacon, S. J. (1996) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19960122)364:4 · Cited by 165 · see citing works
Middle interhemispheric fusion: an unusual variant of holoprosencephaly.
Barkovich, A. J., & Quint, D. J. (1993) · PubMed · Cited by 160 · see citing works
Kato, M., & Dobyns, W. B. (2005) · Journal of Child Neurology · doi:10.1177/08830738050200042001 · Cited by 159 · see citing works
Ascl1 (Mash1) lineage cells contribute to discrete cell populations in CNS architecture.
Kim, E. J., Battiste, J., Nakagawa, Y., & Johnson, J. E. (2008) · Molecular and cellular neurosciences · doi:10.1016/j.mcn.2008.05.008 · Cited by 148 · see citing works
Hevner, R. F. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3180301c06 · Cited by 147 · see citing works
Origins of Cortical GABAergic Neurons in the Cynomolgus Monkey
Petanjek, Z., Berger, B., & Esclapez, M. (2008) · Cerebral Cortex · doi:10.1093/cercor/bhn078 · Cited by 130 · see citing works
Preuss, T. M. (2002) · Cerebral Cortex · doi:10.1093/cercor/12.7.671 · Cited by 108 · see citing works
Patterning the Dorsal Telencephalon: A Role for Sonic Hedgehog?
Rash, B. G., & Grove, E. A. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3204-07.2007 · Cited by 103 · see citing works
Central Roles of the Roof Plate in Telencephalic Development and Holoprosencephaly
Cheng, X., Hsu, C.-M., Currle, D. S., Hu, J. S., Barkovich, A. J., & Monuki, E. S. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0714-06.2006 · Cited by 101 · see citing works
Hof, P. R., Glezer, I. I., Nimchinsky, E. A., & ERWIN, J. M. (2000) · Brain Behavior and Evolution · doi:10.1159/000006665 · Cited by 91 · see citing works
Towards a greater understanding of the pathogenesis of holoprosencephaly
Golden, J. A. (1999) · Brain and Development · doi:10.1016/s0387-7604(99)00067-4 · Cited by 91 · see citing works
The Morphogen Signaling Network in Forebrain Development and Holoprosencephaly
Monuki, E. S. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3180986e1b · Cited by 68 · see citing works
Calcium-Binding Proteins in the Human Developing Brain
Ulfig, N. (2002) · Advances in anatomy, embryology and cell biology · doi:10.1007/978-3-642-59425-0 · Cited by 63 · see citing works
The Prosencephalies: Morphology, Neuroradiological Appearances and Differential Diagnosis
Probst, F. P., Brun, A. E., & Castroviejo, I. P. (1979) · Medical Entomology and Zoology · Cited by 62 · see citing works
DeFelipe, J., Ballesteros‐Yáñez, I., Inda, M. C., & Muñoz, A. (2006) · Progress in brain research · doi:10.1016/s0079-6123(06)54002-6 · Cited by 60 · see citing works
Genetic Control of Neuronal Migrations in Human Cortical Development
Meyer, G. (2007) · Springer eBooks · doi:10.1007/978-3-540-36689-8 · Cited by 55 · see citing works
Cytoplasmic Immunoreactivity for Thyroid Transcription Factor-1 in Hepatocellular Carcinoma
Pan, C., Chen, P. C.-H., Tsay, S., et al. (2004) · American Journal of Clinical Pathology · doi:10.1309/8bm44nk626997djj · Cited by 53 · see citing works
The ups and downs of holoprosencephaly: dorsal versus ventral patterning forces
Fernandes, M., & Hébert, J. M. (2008) · Clinical Genetics · doi:10.1111/j.1399-0004.2008.00994.x · Cited by 51 · see citing works
Distribution of neurons expressing tyrosine hydroxylase in the human cerebral cortex
Benavides‐Piccione, R., & DeFelipe, J. (2007) · Journal of Anatomy · doi:10.1111/j.1469-7580.2007.00760.x · Cited by 45 · see citing works
Probst, F. P. (1979) · Springer eBooks · doi:10.1007/978-3-642-48757-6 · Cited by 44 · see citing works
Ulfig, N. (2002) · Advances in anatomy, embryology and cell biology · doi:10.1007/978-3-642-59425-0_1 · Cited by 41 · see citing works
Perspectives on the Developmental Origins of Cortical Interneuron Diversity
Fishell, G. (2008) · Novartis Foundation symposium · doi:10.1002/9780470994030.ch3 · Cited by 34 · see citing works
Simonati, A., Tosati, C., Rosso, T., Piazzola, E., & Rizzuto, N. (1999) · Microscopy Research and Technique · doi:10.1002/(sici)1097-0029(19990615)45:6 · Cited by 34 · see citing works
Histopathological study of alobar holoprosencephaly
Mizuguchi, M., & Morimatsu, Y. (1989) · Acta Neuropathologica · doi:10.1007/bf00688206 · Cited by 31 · see citing works
Histopathological study of alobar holoprosencephaly
Mizuguchi, M., & Morimatsu, Y. (1989) · Acta Neuropathologica · doi:10.1007/bf00688207 · Cited by 23 · see citing works
Histochemical localization of nitric oxide synthase in the CNS
Šestan, N., & Kostović, I. (1994) · Trends in Neurosciences · doi:10.1016/0166-2236(94)90115-5 · Cited by 19 · see citing works
Self-citationCompartmentalization of NADPH-diaphorase staining in the developing human striatum
Sajin, B., Šestan, N., & Dmitrović, B. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90695-4 · Cited by 17 · see citing works
Self-citationJudáš, M., Rašin, M., Krušlin, B., Kostović, K., Jukić, D., Petanjek, Z., & Kostović, I. (2003) · Brain and Development · doi:10.1016/s0387-7604(02)00149-3 · Cited by 12 · see citing works
Self-citationHoloprosencephaly—Topologic variations in a Liveborn series: A general model based upon MRI analysis
Takahashi, T., Kinsman, S. L., Makris, N., et al. (2004) · Journal of Neurocytology · doi:10.1023/b:neur.0000029646.75645.9c · Cited by 10 · see citing works
Hayashi, M., Araki, S., Kumada, S., et al. (2004) · Acta Neuropathologica · doi:10.1007/s00401-003-0784-0 · Cited by 9 · see citing works
Self-citationHoloprosencephaly in deletions of proximal chromosome 14q.
Devriendt, K., Fryns, J. P., & Chen, C. (1998) · Journal of Medical Genetics · doi:10.1136/jmg.35.7.612 · Cited by 8 · see citing works
Ectopic expression of telencephalin in brains with holoprosencephaly
Arii, N., Mizuguchi, M., Mori, K., et al. (2000) · Acta Neuropathologica · doi:10.1007/s004010000184 · Cited by 3 · see citing works
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Rakic, P. (2009) · Nature reviews. Neuroscience · doi:10.1038/nrn2719 · Cited by 1,565 · see citing works
Development and Evolution of the Human Neocortex
Lui, J. H., Hansen, D. V., & Kriegstein, A. R. (2011) · Cell · doi:10.1016/j.cell.2011.06.030 · Cited by 1,342 · see citing works
The Cellular and Molecular Landscapes of the Developing Human Central Nervous System
Silbereis, J. C., Pochareddy, S., Zhu, Y., Li, M., & Sestan, N. (2016) · Neuron · doi:10.1016/j.neuron.2015.12.008 · Cited by 818 · see citing works
Development of prefrontal cortex
Kolk, S. M., & Rakic, P. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-021-01137-9 · Cited by 378 · see citing works
“Furthermore, it appears that nonhuman primates and humans have distinct populations of GABAergic neurons which originate in proliferative zones of the dorsal telencephalon [193, 194].”
BackgroundFung, S. J., Webster, M. J., Sivagnanasundaram, S., Duncan, C., Elashoff, M., & Weickert, C. S. (2010) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2010.09060784 · Cited by 366 · see citing works
Non-epithelial stem cells and cortical interneuron production in the human ganglionic eminences
Hansen, D. V., Lui, J. H., Flandin, P., Yoshikawa, K., Rubenstein, J. L., Alvarez-Buylla, A., & Kriegstein, A. R. (2013) · Nature Neuroscience · doi:10.1038/nn.3541 · Cited by 328 · see citing works
Subcortical origins of human and monkey neocortical interneurons
Ma, T., Wang, C., Wang, L., Zhou, X., Tian, M., Zhang, Q., Zhang, Y., Li, J., Liu, Z., Cai, Y., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3536 · Cited by 322 · see citing works
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Jakovcevski, I. (2009) · Frontiers in Neuroanatomy · doi:10.3389/neuro.05.005.2009 · Cited by 323 · see citing works
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Dehay, C., Kennedy, H., & Kosik, K. S. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.060 · Cited by 314 · see citing works
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Hu, J. S., Vogt, D., Sandberg, M., & Rubenstein, J. L. (2017) · Development · doi:10.1242/dev.132852 · Cited by 189 · see citing works
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Catts, V. S., Fung, S. J., Long, L. E., Joshi, D., Vercammen, A., Allen, K. M., Fillman, S. G., Rothmond, D. A., Sinclair, D., Tiwari, Y., et al. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00060 · Cited by 206 · see citing works
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Vasung, L., Abaci Turk, E., Ferradal, S. L., Sutin, J., Stout, J. N., Ahtam, B., Lin, P.-Y., & Grant, P. E. (2019) · NeuroImage · doi:10.1016/j.neuroimage.2018.07.041 · Cited by 177 · see citing works
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Kwan, K. Y., Lam, M. M. S., Johnson, M. B., Dube, U., Shim, S., Rašin, M.-R., Sousa, A. M. M., Fertuzinhos, S., Chen, J.-G., Arellano, J. I., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.060 · Cited by 137 · see citing works
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- Authors
- Fertuzinhos, S., Krsnik, Ž., Kawasawa, Y. I., Rašin, M.-R., Kwan, K. Y., Chen, J.-G., Judaš, M., Hayashi, M., & Šestan, N.
- Affiliations
- Yale University (US)
- ORCID
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-02-20
- Volume
- 19
- Issue
- 9
- Pages
- 2196-2207
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- PMC
- PMC2722430
- OpenAlex
- W2096070762
- Cited by
- 106
- References
- 56
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 6 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 7 · 2015: 3 · 2014: 15 · 2013: 15 · 2012: 9
- FWCI
- 3.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cerebral Cortex (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Autism Speaks
- State Key Laboratory of Automotive Simulation and Control
- National Institutes of Health
- Canadian Institutes of Health Research
- National Institute of Neurological Disorders and Stroke (R01NS054273, NS 054273)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD045481, HD045481)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- holoprosencephaly, cortical interneurons, nitric oxide synthase 1, neuropeptide Y, somatostatin, calretinin, interneuron migration, GABAergic interneurons, glutamatergic projection neurons, fetal brain development
- MeSH terms
- Cerebral Cortex, Corpus Striatum, Humans, Infant, Newborn, Interneurons, Holoprosencephaly, Neurotransmitter Agents
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