<i>Coup-TF1</i> and <i>Coup-TF2</i> control subtype and laminar identity of MGE-derived neocortical interneurons

Hu, Jiang; Vogt, Daniel; Lindtner, Susan; Sandberg, Magnus; Silberberg, Shanni N.; Rubenstein, John L.R.

doi:10.1242/dev.150664

Cited by 62 publications

(89 citation statements)

References 55 publications

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“…The pattern of expression we observed here mirror descriptions of other studies of NR2F2 expression in the rodent hippocampus [22], as well as more macroscopically in the human brain during development, particularly in the temporal lobes [4]. NR2F2 is also key in the determination of cell fate in numerous circumstances [32, 27], including that of interneurons expressing PVALB (parvalbumin) or SST (somatostatin), where NR2F2 promotes SST and represses PVALB [27]. These findings are highly consistent with the expression of PVALB (expressed posteriorly) and SSTR1 (expressed anteriorly with NR2F2) in our data (Table 1).…”

Section: Discussionsupporting

confidence: 85%

A molecular gradient along the longitudinal axis of the human hippocampus informs large-scale behavioral systems

Vogel

Joie

Grothe

et al. 2019

Preprint

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The functional organization of the hippocampus is distributed as a gradient along its longitudinal axis that explains its differential interaction with diverse brain systems. We show that the location of human tissue samples extracted along the longitudinal axis of the hippocampus can be predicted within 2mm using the expression pattern of less than 100 genes. When variation in this specific gene expression pattern was observed across the whole brain, a distinct anterioventral-posteriodorsal gradient was observed. Frontal, anterior temporal and brainstem regions involved in social and motivational behaviors, selectively vulnerable to frontotemporal dementia and more functionally connected to the anterior hippocampus could be clearly differentiated from posterior parieto-occipital and cerebellar regions involved in spatial cognition, selectively vulnerable to Alzheimers disease, and more functionally connected to the posterior hippocampus. These findings place the human hippocampus at the interface of two major brain systems defined by a single distinct molecular gradient. (148/150) A phylogenetically conserved and well connected structure involved in a 2 diverse multitude of behaviors, the hippocampus provides an excellent base 3 for studying the evolution of cognition. Alongside its highly nuanced and 4 well documented role in memory, the hippocampus has been implicated in 5 many other behaviors and functions, ranging from social cognition to spatial 6 orientation to regulation of endocrine processes, such as stress response [5, 8]. 7The hippocampus can be divided into well-described subfields -the cornu 8 ammoni (CA), dentate gyrus and subiculum -which represent its principal 9 axis of organization, and which strongly inform cytoarchitectonic variation 10 and both internal and external circuitry [5]. A second orthogonal axis of 11 organization of the hippocampus lies along its longitudinal axis in a gradi-12 ent spanning its two poles. In the rodent, this axis is often referred to as 13 the ventral-dorsal axis, while a homologous gradient is thought to exist in 14 humans along the anterior-posterior axis [49, 20, 42]. To study variations 15 along this axis, the hippocampus is often divided into basic macroscopic 16 partitions; the head-body-tail division is often used in humans, whereas a 17 dorsal-ventral division is used in rodents. The divisions along the longitu-18 dinal axis of the hippocampus are characterized by a complex but distinct 19 pattern of afferent and efferent connections, as well as impressive behavioral 20 domain specificity. In rodents, the ventral hippocampus shares connections 21 with the prefrontal cortex, basolateral amygdala, hypothalamus, and other 22 structures mediating neuroendocrine and autonomic signaling and motivated 23 behavior. Meanwhile, the dorsal hippocampus is anatomically connected 24 with retrosplenial cortex, mamillary bodies, anterior thalamic complex and 25 other networks implicated in movement, navigation and exploration ([8, 20]). 26 Studies directly assessing the e...

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Section: Discussionsupporting

confidence: 85%

A molecular gradient along the longitudinal axis of the human hippocampus informs large-scale behavioral systems

Vogel

Joie

Grothe

et al. 2019

Preprint

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“…S2A), and the regulation of Pax6 by MEIS1 has been independently validated recently (Owa et al 2018). The RA signal propagates further through PAX6 to activate interneuron-related genes Nr2f2 and Nr2f1 (Hu et al 2017). .…”

Section: Grn-loop Reveals Driver Tfs and Cis-regulatory Dna Elementsmentioning

confidence: 90%

Gene regulatory network reconstruction incorporating 3D chromosomal architecture reveals key transcription factors and DNA elements driving neural lineage commitment

Malysheva¹,

Mendoza-Parra

Blum

et al. 2018

Preprint

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Lineage commitment is a fundamental process that enables the morphogenesis of multicellular organisms from a single pluripotent cell. While many genes involved in the commitment to specific lineages are known, the logic of their joint action is incompletely understood, and predicting the effects of genetic perturbations on lineage commitment is still challenging. Here, we devised a gene regulatory network analysis approach, GRN-loop, to identify key cisregulatory DNA elements and transcription factors that drive lineage commitment. GRN-loop is based on signal propagation and combines transcription factor binding data with the temporal profiles of gene expression, chromatin state and 3D chromosomal architecture. Applying GRN-loop to a model of morphogen-induced early neural lineage commitment, we discovered a set of driver transcription factors and enhancers, some of them validated in recent data and others hitherto unknown. Our work provides the basis for an integrated understanding of neural lineage commitment, and demonstrates the potential of gene regulatory network analyses informed by 3D chromatin architecture to uncover the key genes and regulatory elements driving developmental processes.

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“…This study suggests new ideas about how some aspects of CIN cell fate and function are regulated, particularly in post-mitotic/maturing CINs. Previous studies identified TFs that are expressed in SST+ CINs but not in PV+ CINs, as well as TFs that can alter the ratios of SST+ and PV+ CINs [22][23][24]27,[56][57][58] . Of note, we are not aware of a TF that is uniquely expressed in PV+ but not SST+ CINs 59 .…”

Section: Discussionmentioning

confidence: 99%

The Tuberous Sclerosis gene, Tsc1, represses parvalbumin+/fast-spiking properties in somatostatin-lineage cortical interneurons

Malik

Pai

Rubin

et al. 2019

Preprint

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Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. However, mechanisms regulating their diversity remain poorly understood. Here, we show that conditional loss of the Tuberous Sclerosis (TS) gene, Tsc1, which inhibits mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs. These changes also occur when only one allele of Tsc1 is deleted, making these findings relevant to individuals with TS. Notably, treatment with rapamycin, which inhibits MTOR, reverses these changes in adult mice. These data reveal novel functions of MTOR signaling in regulating PV expression and FS properties, which may contribute to some neuropsychiatric symptoms observed in TS. Moreover, they suggest that CINs can exhibit properties intermediate between those classically associated with PV+ or SST+ CINs, which may be dynamically regulated by the MTOR signaling.

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Coup-TF1 and Coup-TF2 control subtype and laminar identity of MGE-derived neocortical interneurons

Cited by 62 publications

References 55 publications

A molecular gradient along the longitudinal axis of the human hippocampus informs large-scale behavioral systems

A molecular gradient along the longitudinal axis of the human hippocampus informs large-scale behavioral systems

Gene regulatory network reconstruction incorporating 3D chromosomal architecture reveals key transcription factors and DNA elements driving neural lineage commitment

The Tuberous Sclerosis gene, Tsc1, represses parvalbumin+/fast-spiking properties in somatostatin-lineage cortical interneurons

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