scholarly journals A transient role of primary cilia in controlling direct versus indirect neurogenesis in the developing cerebral cortex

2020 ◽  
Author(s):  
Kerstin Hasenpusch-Theil ◽  
Christine Laclef ◽  
Matt Colligan ◽  
Eamon Fitzgerald ◽  
Katherine Howe ◽  
...  

ABSTRACTDuring the development of the cerebral cortex, neurons are generated directly from radial glial cells or indirectly via basal progenitors. The balance between these division modes determines the number and types of neurons formed in the cortex thereby affecting cortical functioning. Here, we investigate the role of primary cilia in this process. We show that a mutation in the ciliary gene Inpp5e leads to a transient increase in direct neurogenesis and subsequently to an overproduction of layer V neurons in newborn mice. Loss of Inpp5e also affects ciliary structure coinciding with increased Akt and mTOR signalling and reduced Gli3 repressor levels. Genetically re-storing Gli3 repressor rescues the decreased indirect neurogenesis in Inpp5e mutants. Overall, our analyses reveal how primary cilia determine neuronal subtype composition of the cortex by controlling direct vs indirect neurogenesis. These findings have implications for understanding cortical malformations in ciliopathies with INPP5E mutations.

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Kerstin Hasenpusch-Theil ◽  
Christine Laclef ◽  
Matt Colligan ◽  
Eamon Fitzgerald ◽  
Katherine Howe ◽  
...  

During the development of the cerebral cortex, neurons are generated directly from radial glial cells or indirectly via basal progenitors. The balance between these division modes determines the number and types of neurons formed in the cortex thereby affecting cortical functioning. Here, we investigate the role of primary cilia in controlling the decision between forming neurons directly or indirectly. We show that a mutation in the ciliary gene Inpp5e leads to a transient increase in direct neurogenesis and subsequently to an overproduction of layer V neurons in newborn mice. Loss of Inpp5e also affects ciliary structure coinciding with reduced Gli3 repressor levels. Genetically restoring Gli3 repressor rescues the decreased indirect neurogenesis in Inpp5e mutants. Overall, our analyses reveal how primary cilia determine neuronal subtype composition of the cortex by controlling direct versus indirect neurogenesis. These findings have implications for understanding cortical malformations in ciliopathies with INPP5E mutations.


Development ◽  
1997 ◽  
Vol 124 (18) ◽  
pp. 3501-3510 ◽  
Author(s):  
E.S. Anton ◽  
M.A. Marchionni ◽  
K.F. Lee ◽  
P. Rakic

During neuronal migration to the developing cerebral cortex, neurons regulate radial glial cell function and radial glial cells, in turn, support neuronal cell migration and differentiation. To study how migrating neurons and radial glial cells influence each others' function in the developing cerebral cortex, we examined the role of glial growth factor (a soluble form of neuregulin), in neuron-radial glial interactions. Here, we show that GGF is expressed by migrating cortical neurons and promotes their migration along radial glial fibers. Concurrently, GGF also promotes the maintenance and elongation of radial glial cells, which are essential for guiding neuronal migration to the cortex. In the absence of GGF signaling via erbB2 receptors, radial glial development is abnormal. Furthermore, GGF's regulation of radial glial development is mediated in part by brain lipid-binding protein (BLBP), a neuronally induced, radial glial molecule, previously shown to be essential for the establishment and maintenance of radial glial fiber system. The ability of GGF to influence both neuronal migration and radial glial development in a mutually dependent manner suggests that it functions as a mediator of interactions between migrating neurons and radial glial cells in the developing cerebral cortex.


2014 ◽  
Vol 27 ◽  
pp. 39-46 ◽  
Author(s):  
Víctor Borrell ◽  
Magdalena Götz

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mariko Umemura ◽  
Yasuyuki Kaneko ◽  
Ryoko Tanabe ◽  
Yuji Takahashi

AbstractActivating transcription factor 5 (ATF5) is a member of the cAMP response element binding protein (CREB)/ATF family of basic leucine zipper transcription factors. We previously reported that ATF5-deficient (ATF5−/−) mice exhibited behavioural abnormalities, including abnormal social interactions, reduced behavioural flexibility, increased anxiety-like behaviours, and hyperactivity in novel environments. ATF5−/− mice may therefore be a useful animal model for psychiatric disorders. ATF5 is highly expressed in the ventricular zone and subventricular zone during cortical development, but its physiological role in higher-order brain structures remains unknown. To investigate the cause of abnormal behaviours exhibited by ATF5−/− mice, we analysed the embryonic cerebral cortex of ATF5−/− mice. The ATF5−/− embryonic cerebral cortex was slightly thinner and had reduced numbers of radial glial cells and neural progenitor cells, compared to a wild-type cerebral cortex. ATF5 deficiency also affected the basal processes of radial glial cells, which serve as a scaffold for radial migration during cortical development. Further, the radial migration of cortical upper layer neurons was impaired in ATF5−/− mice. These results suggest that ATF5 deficiency affects cortical development and radial migration, which may partly contribute to the observed abnormal behaviours.


Glia ◽  
2015 ◽  
Vol 63 (8) ◽  
pp. 1303-1319 ◽  
Author(s):  
Camino De Juan Romero ◽  
Víctor Borrell

2021 ◽  
Author(s):  
Leah Schembs ◽  
Ariane Willems ◽  
Kerstin Hasenpusch-Theil ◽  
James D Cooper ◽  
Katie Whiting ◽  
...  

Defects in primary cilia, cellular antennas that controls multiple intracellular signalling pathways, underlie several neurodevelopmental disorders, but how cilia control essential steps in human brain formation remains elusive. Here, we show that cilia are present on the apical surface of radial glial cells in human foetal forebrain. Interfering with cilia signalling in human organoids by mutating the INPP5E gene leads to the formation of ventral telencephalic cell types instead of cortical progenitors and neurons. INPP5E mutant organoids also showed increased SHH signalling and cyclopamine treatment partially rescued this ventralisation. In addition, ciliary expression of SMO was increased and the integrity of the transition zone was compromised. Overall, these findings establish the importance of primary cilia for dorsal/ventral patterning in human corticogenesis, indicate a tissue specific role of INPP5E as a negative regulator of SHH signalling and have implications for the emerging roles of cilia in the pathogenesis of neurodevelopmental disorders.


2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Kunzhao Du ◽  
Zhen Zhang ◽  
Zhiwei Zeng ◽  
Jinling Tang ◽  
Trevor Lee ◽  
...  

AbstractProper development of the mammalian cerebral cortex relies on precise gene expression regulation, which is controlled by genetic, epigenetic, and epitranscriptomic factors. Here we generate RNA demethylase Fto and methyltransferase Mettl3 cortical-specific conditional knockout mice, and detect severe brain defects caused by Mettl3 deletion but not Fto knockout. Transcriptomic profiles using RNA sequencing indicate that knockout of Mettl3 causes a more dramatic alteration on gene transcription than that of Fto. Interestingly, we conduct ribosome profiling sequencing, and find that knockout of Mettl3 leads to a more severe disruption of translational regulation of mRNAs than deletion of Fto and results in altered translation of crucial genes in cortical radial glial cells and intermediate progenitors. Moreover, Mettl3 deletion causes elevated translation of a significant number of mRNAs, in particular major components in m6A methylation. Our findings indicate distinct functions of Mettl3 and Fto in brain development, and uncover a profound role of Mettl3 in regulating translation of major mRNAs that control proper cortical development.


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