Ben Barres (1954-2017) Cayouette, Michel
Development,
03/2018, Volume:
145, Issue:
6
Journal Article
Peer reviewed
Open access
Ben Barres changed our view of glial cell function and impacted the lives of many people who interacted with him. Remembering an outstanding scientist and mentor.
Neural progenitors alter their output over time to generate different types of neurons and glia in specific chronological sequences, but this process remains poorly understood in vertebrates. Here we ...show that Casz1, the vertebrate ortholog of the Drosophila temporal identity factor castor, controls the production of mid-/late-born neurons in the murine retina. Casz1 is expressed from mid/late stages in retinal progenitor cells (RPCs), and conditional deletion of Casz1 increases production of early-born retinal neurons at the expense of later-born fates, whereas precocious misexpression of Casz1 has the opposite effect. In both cases, cell proliferation is unaffected, indicating that Casz1 does not control the timing of cell birth but instead biases RPC output directly. Just as Drosophila castor lies downstream of the early temporal identity factor hunchback, we find that the hunchback ortholog Ikzf1 represses Casz1. These results uncover a conserved strategy regulating temporal identity transitions from flies to mammals.
•Casz1 expression is upregulated in mid-/late-stage retinal progenitors•Casz1 is required to suppress early-born retinal fate production•Ectopic expression of Casz1 promotes mid-/late-born neuronal fates•Casz1 is repressed by Ikzf1, analogously to Drosophila castor by hunchback
How neural progenitors alter their output over time remains unclear in vertebrates. Mattar et al. identify Casz1 as a key regulator of temporal progression in retinal progenitors and provide evidence for conservation of the transcriptional cascade strategy used in Drosophila neuroblasts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Sound perception relies on the planar polarization of the mechanosensory hair cell apex, which develops a V-shaped stereocilia bundle pointing toward an eccentric kinocilium. It remains unknown how ...intrinsically asymmetric bundles arise and are concomitantly oriented in the tissue. We report here that mInsc, LGN, and Gαi proteins, which classically regulate mitotic spindle orientation, are polarized in a lateral microvilli-free region, or “bare zone,” at the apical hair cell surface. By creating and extending the bare zone, these proteins trigger a relocalization of the eccentric kinocilium midway toward the cell center. aPKC is restrained medially by mInsc/LGN/Gαi, resulting in compartmentalization of the apical surface that imparts the V-shaped distribution of stereocilia and brings the asymmetric bundle in register with the relocalized kinocilium. Gαi is additionally required for lateral orientation of cochlear hair cells, providing a possible mechanism to couple the emergence of asymmetric stereocilia bundles with planar cell polarity.
•mInsc/LGN/Gαi control the formation of a microvilli-free domain at hair cell apex•Extension of microvilli-free domain triggers inward relocalization of the kinocilium•mInsc/LGN/Gαi restrain aPKC medially, thereby defining the stereocilia bundle edge•Gαi signaling is also required for proper orientation of hair cells in the cochlea
Auditory function requires asymmetric localization of stereocilia at the apical surface of cochlear hair cells. Tarchini et al. show that opposition between mitotic spindle orientation proteins mInsc/LGN/Gαi and the polarity kinase aPKC controls the formation of a polarized microvilli-free domain and thus defines a blueprint for the V-shaped stereocilia bundle.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neural progenitor cells undergo identity transitions during development to ensure the generation different types of neurons and glia in the correct sequence and proportions. A number of temporal ...identity factors that control these transitions in progenitor competence have been identified, but the molecular mechanisms underlying their function remain unclear. Here, we asked how Casz1, the mammalian orthologue of Drosophila castor, regulates competence during retinal development. We show that Casz1 is required to control the transition between neurogenesis and gliogenesis. Using BioID proteomics, we reveal that Casz1 interacts with the nucleosome remodeling and deacetylase (NuRD) complex in retinal cells. Finally, we show that both the NuRD and the polycomb repressor complexes are required for Casz1 to promote the rod fate and suppress gliogenesis. As additional temporal identity factors have been found to interact with the NuRD complex in other contexts, we propose that these factors might act through this common biochemical process to regulate neurogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Sensory perception in the inner ear relies on the hair bundle, the highly polarized brush of movement detectors that crowns hair cells. We previously showed that, in the mouse cochlea, the edge of ...the forming bundle is defined by the 'bare zone', a microvilli-free sub-region of apical membrane specified by the Insc-LGN-Gαi protein complex. We now report that LGN and Gαi also occupy the very tip of stereocilia that directly abut the bare zone. We demonstrate that LGN and Gαi are both essential for promoting the elongation and differential identity of stereocilia across rows. Interestingly, we also reveal that total LGN-Gαi protein amounts are actively balanced between the bare zone and stereocilia tips, suggesting that early planar asymmetry of protein enrichment at the bare zone confers adjacent stereocilia their tallest identity. We propose that LGN and Gαi participate in a long-inferred signal that originates outside the bundle to model its staircase-like architecture, a property that is essential for direction sensitivity to mechanical deflection and hearing.
Retinal degenerative diseases, which lead to the death of rod and cone photoreceptor cells, are the leading cause of inherited vision loss worldwide. Induced pluripotent or embryonic stem cells ...(iPSCs/ESCs) have been proposed as a possible source of new photoreceptors to restore vision in these conditions. The proof of concept studies carried out in mouse models of retinal degeneration over the past decade have highlighted several limitations for cell replacement in the retina, such as the low efficiency of cone photoreceptor production from stem cell cultures and the poor integration of grafted cells in the host retina. Current protocols to generate photoreceptors from stem cells are largely based on the use of extracellular factors. Although these factors are essential to induce the retinal progenitor cell (RPC) fate from iPSCs/ESCs, developmental studies have shown that RPCs alter fate output as a function of time (i.e., their temporal identity) to generate the seven major classes of retinal cell types, rather than spatial position. Surprisingly, current stem cell differentiation protocols largely ignore the intrinsic temporal identity of dividing RPCs, which we argue likely explains the low efficiency of cone production in such cultures. In this article, we briefly review the mechanisms regulating temporal identity in RPCs and discuss how they could be exploited to improve cone photoreceptor production for cell replacement therapies.
The balance of contralateral and ipsilateral retinogeniculate projections is critical for binocular vision, but the transcriptional programs regulating this process remain ill defined. Here we show ...that the Pou class homeobox protein POU3F1 is expressed in nascent mouse contralateral retinal ganglion cells (cRGCs) but not ipsilateral RGCs (iRGCs). Upon Pou3f1 inactivation, the proportion of cRGCs is reduced in favor of iRGCs, leading to abnormal projection ratios at the optic chiasm. Conversely, misexpression of Pou3f1 in progenitors increases the production of cRGCs. Using CUT&RUN and RNA sequencing in gain- and loss-of-function assays, we demonstrate that POU3F1 regulates expression of several key members of the cRGC gene regulatory network. Finally, we report that POU3F1 is sufficient to induce RGC-like cell production, even in late-stage retinal progenitors of Atoh7 knockout mice. This work uncovers POU3F1 as a regulator of the cRGC transcriptional program, opening possibilities for optic nerve regenerative therapies.
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•POU3F1 is expressed in postmitotic RGC precursors but downregulated in most mature RGCs•Pou3f1 loss increases production of ipsilateral RGCs at the expense of contralateral RGCs•POU3F1 represses ipsilateral determinants and activates contralateral determinants•POU3F1 promotes RGC-like cell production when misexpressed in late progenitors
Fries et al. demonstrate that POU3F1 is expressed in postmitotic retinal ganglion cell (RGC) precursors, where it represses Atoh7 and the ipsilateral determinant Zic2, while promoting expression of several contralateral determinants, leading to the generation of contralateral RGCs. This work uncovers a developmental regulator of cells involved in binocular vision.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The visual system consists of two major subsystems, image-forming circuits that drive conscious vision and non-image-forming circuits for behaviors such as circadian photoentrainment. While ...historically considered non-overlapping, recent evidence has uncovered crosstalk between these subsystems. Here, we investigated shared developmental mechanisms. We revealed an unprecedented role for light in the maturation of the circadian clock and discovered that intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical for this refinement process. In addition, ipRGCs regulate retinal waves independent of light, and developmental ablation of a subset of ipRGCs disrupts eye-specific segregation of retinogeniculate projections. Specifically, a subset of ipRGCs, comprising ~200 cells and which project intraretinally and to circadian centers in the brain, are sufficient to mediate both of these developmental processes. Thus, this subset of ipRGCs constitute a shared node in the neural networks that mediate light-dependent maturation of the circadian clock and light-independent refinement of retinogeniculate projections.
During cerebral cortex development, a series of projection neuron types is generated in a fixed temporal order. In Drosophila neuroblasts, the transcription factor hunchback encodes first-born ...identity within neural lineages. One of its mammalian homologs, Ikaros, was recently reported to play an equivalent role in retinal progenitor cells, raising the question as to whether Ikaros/Hunchback proteins could be general factors regulating the development of early-born fates throughout the nervous system. Ikaros is also expressed in progenitor cells of the mouse cerebral cortex, and this expression is highest during the early stages of neurogenesis and thereafter decreases over time. Transgenic mice with sustained Ikaros expression in cortical progenitor cells and neurons have developmental defects, including displaced progenitor cells within the cortical plate, increased early neural differentiation, and disrupted cortical lamination. Sustained Ikaros expression results in a prolonged period of generation of deep layer neurons into the stages when, normally, only late-born upper layer neurons are generated, as well as a delayed production of late-born neurons. Consequently, more early-born and fewer late-born neurons are present in the cortex of these mice at birth. This phenotype was observed in all parts of the cortex, including those with minimal structural defects, demonstrating that it is not secondary to abnormalities in cortical morphogenesis. These data suggest that Ikaros plays a similar role in regulating early temporal fates in the mammalian cerebral cortex as Ikaros/Hunchback proteins do in the Drosophila nerve cord.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
During development, Shh attracts commissural axons toward the floor plate through a non-canonical, transcription-independent signaling pathway that requires the receptor Boc. Here, we find that Shh ...induces Boc internalization into early endosomes and that endocytosis is required for Shh-mediated growth-cone turning. Numb, an endocytic adaptor, binds to Boc and is required for Boc internalization, Shh-mediated growth-cone turning in vitro, and commissural axon guidance in vivo. Similar to Boc, Ptch1 is also internalized by Shh in a Numb-dependent manner; however, the binding of Shh to Ptch1 alone is not sufficient to induce Ptch1 internalization nor growth-cone turning. Therefore, the binding of Shh to Boc is required for Ptch1 internalization and growth-cone turning. Our data support a model where Boc endocytosis via Numb is required for Ptch1 internalization and Shh signaling in axon guidance. Thus, Boc acts as a Shh-dependent endocytic platform gating Ptch1 internalization and Shh signaling.
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•Sonic hedgehog (Shh) induces endocytosis of Boc and Ptch1 into Rab5 endosomes•The endocytic adaptor Numb binds to Boc and is required for Boc endocytosis•Numb is required for Shh-mediated axon attraction in vitro and axon guidance in vivo•Binding of Shh to Boc is required for Ptch1 endocytosis and Shh axon attraction
Ferent et al. elucidate how the Shh receptor Boc works together with Ptch1 to transduce the Shh signal in axon guidance. They demonstrate that Numb-mediated internalization of Boc is required for Ptch1 internalization, activation of signaling, and Shh-mediated axon guidance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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