Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice

Laclef

Colligan

et al. 2020

eLife

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.

Section: Discussionmentioning

confidence: 69%

A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development

Laclef

Colligan

et al. 2020

eLife

“…Finally, the corpus callosum is thinner but callosal axons normally project to the contralateral cerebral hemisphere in Inpp5e mutants. This phenotype is milder compared to that of other mouse mutants with altered cilia that show complete agenesis of the corpus callosum with callosal axons forming Probst bundles (Benadiba et al, 2012; Laclef et al, 2015; Putoux et al, 2019). Unlike these other ciliary mutants, the corticoseptal boundary which plays a crucial role in positioning guidepost cells that control midline crossing of callosal axons (Magnani et al, 2014) is not obviously affected in Inpp5e Δ/Δ embryos.…”

Section: Discussionmentioning

confidence: 69%

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

Laclef

Colligan

et al. 2020

Preprint

23 24 25 26 27 2 ABSTRACT 28 29During the development of the cerebral cortex, neurons are generated directly from radial glial cells 30 or indirectly via basal progenitors. The balance between these division modes determines the 31 number and types of neurons formed in the cortex thereby affecting cortical functioning. Here, we 32 investigate the role of primary cilia in this process. We show that a mutation in the ciliary gene Inpp5e 33 leads to a transient increase in direct neurogenesis and subsequently to an overproduction of layer 34 V neurons in newborn mice. Loss of Inpp5e also affects ciliary structure coinciding with increased 35 Akt and mTOR signalling and reduced Gli3 repressor levels. Genetically re-storing Gli3 repressor 36 rescues the decreased indirect neurogenesis in Inpp5e mutants. Overall, our analyses reveal how 37 primary cilia determine neuronal subtype composition of the cortex by controlling direct vs indirect 38 neurogenesis. These findings have implications for understanding cortical malformations in 39 ciliopathies with INPP5E mutations.40 41 101 rescues the decreased formation of basal progenitors. Taken together, these findings implicate the 102 primary cilium in controlling the decision of RGCs to either undergo direct neurogenesis or to form 103 basal progenitors, thereby governing the neuronal subtype composition of the cerebral cortex. 104 105 5 RESULTS 106 107 Inpp5e  embryos show mild telencephalic patterning defects 108 Controlling the balance between direct and indirect neurogenesis in the developing cerebral 109 cortex is mediated by cell-cell signaling (Cardenas et al., 2018) and is hence likely to involve the 110 primary cilium. To investigate potential ciliary roles, we started characterizing cortical stem cell 111 development in embryos mutant for the Inpp5e gene which has a prominent role in ciliary signaling 112 and stability. Mutations in ciliary genes have previously been found to result in telencephalon 113 patterning defects, most notably in a ventralisation of the dorsal telencephalon and/or in defects at 114 the corticoseptal (CSB) and pallial/subpallial boundaries (PSPB) (Ashique et al., 2009; Besse et al., 115 2011; Willaredt et al., 2008). Therefore, we first considered the possibility that such early patterning 116 defects may be present in Inpp5e mutant embryos and could affect cortical stem cell development. 117 In situ hybridization and immunofluorescence analyses of E12.5 control and Inpp5e  embryos 118 revealed no obvious effect on the expression of dorsal and ventral telencephalic markers at the 119 corticoseptal boundary (SupFig. 1). In contrast, the pallial/subpallial boundary was not well defined 120 with a few scattered Pax6+ and Dlx2 expressing cells on the wrong side of the boundary, i.e. in the 121 subpallium and pallium, respectively (SupFig. 1). Moreover, the hippocampal anlage appeared 122 smaller and disorganized with low level and diffuse expression of cortical hem markers (SupFig. 2), 123 consistent with known roles of Wnt/-catenin and...

“…underlying mechanisms were not further investigated. Detailed mechanistic insights into the role of primary cilia in midline crossing came from the analyses of Rfx3, Rpgrip1l, and Kif7 mutant mice (Benadiba et al, 2012;Laclef et al, 2015;Putoux et al, 2019). Rfx3 encodes a transcription factor controlling the expression of many genes involved in ciliary assembly and function (Thomas et al, 2010); RPGRIP1L is mutated in Joubert and Meckel Gruber Syndromes (Arts et al, 2007;Delous et al, 2007) and codes for a transition zone protein.…”

Section: Primary Cilia and Axon Pathfinding In The Cerebral Cortexmentioning

confidence: 99%

The Multifaceted Roles of Primary Cilia in the Development of the Cerebral Cortex

Theil

2021

Front. Cell Dev. Biol.

The primary cilium, a microtubule based organelle protruding from the cell surface and acting as an antenna in multiple signaling pathways, takes center stage in the formation of the cerebral cortex, the part of the brain that performs highly complex neural tasks and confers humans with their unique cognitive capabilities. These activities require dozens of different types of neurons that are interconnected in complex ways. Due to this complexity, corticogenesis has been regarded as one of the most complex developmental processes and cortical malformations underlie a number of neurodevelopmental disorders such as intellectual disability, autism spectrum disorders, and epilepsy. Cortical development involves several steps controlled by cell–cell signaling. In fact, recent findings have implicated cilia in diverse processes such as neurogenesis, neuronal migration, axon pathfinding, and circuit formation in the developing cortex. Here, we will review recent advances on the multiple roles of cilia during cortex formation and will discuss the implications for a better understanding of the disease mechanisms underlying neurodevelopmental disorders.