Biology subjects

Cayouette, M.

Publications and source records attributed to Cayouette, M..

11 recordsLinked to original sources

bioRxiv2026

Foxp1 Coordinates Early Temporal Identity and Neurogenic Progression in Retinal Progenitors

Neural diversity depends on both the temporal competence of progenitors to generate particular cell types and their progression into a neurogenic state. How these distinct features of progenitor development are mechanistically coordinated remains poorly understood. Here, we identify Foxp1 as a dual function transcriptional regulator that couples early progenitor identity to neurogenic progression in the developing retina. By defining its direct transcriptional targets, we show that Foxp1 coordinates complementary regulatory programs: it sustains early competence by activating early-stage retinal progenitor genes and repressing late temporal factors, while promoting neurogenic progression through activation of the proneural factors Atoh7 and Neurog2. We establish a cis-regulatory mechanism linking these functions: Foxp1 activates Atoh7 through its remote shadow enhancer, and deletion of this enhancer prevents Foxp1-dependent induction of Atoh7 and retinal ganglion cell (RGC) production. We further reveal that Neurog2 partially compensates for loss of Atoh7 function. This coordinated early progenitor program is temporally restricted by progressive silencing of Foxp1, involving sequential deposition of H2AK119ub1 followed by H3K27me3 at a distal conserved silencer essential for its repression. Together, these findings establish a mechanistic link between temporal competence and neurogenic progression, revealing how a shared transcriptional regulator coordinates progenitor identity with neuronal production through distinct cis-regulatory elements.

developmental biology↗

bioRxiv2026

A Müller glia-retinal pigment epithelium apical network surrounding cone outer segments in fish and mouse

Homeostasis of the vertebrate retina is supported by two non-neuronal cell types, Muller glia and the retinal pigment epithelium (RPE). Their apical domains delineate the subretinal space, where photoreceptor outer segments reside. While the individual interactions between the supporting cells and photoreceptors are well studied, Muller glia and RPE are presumed to remain physically separate in a healthy retina. Here, we describe a revised model of the subretinal space architecture based on detailed FIB-SEM and confocal microscopy imaging of the zebrafish and mouse outer retina. Long apical processes extend from both Muller glia and the RPE, interacting with one another while also encircling cone outer segments. These contact regions, at the interface of the three cell types are highly elaborated in fish and, although sparser, are still present in mouse. The growth and overlap of Muller glial and RPE apical processes occurs subsequent to the emergence of the outer segment in both species, and coincides with the onset of visual function in mouse. Although enriched at cone sites, this specialized interaction does not appear to depend solely on cone localization in either species, pointing to a general hallmark of the vertebrate subretinal space. Together, our work provides major insights into the architecture of the subretinal space and the interactions between Muller glia, RPE and photoreceptors, while demonstrating conservation across species.

cell biology↗

bioRxiv2024

Cadherin 4 assembles a family of color-selective retinal circuits that respond to light offset.

Retinal interneurons and projection neurons (retinal ganglion cells, RGCs) connect in specific combinations in a specialized neuropil called the inner plexiform layer (IPL). The IPL is divided into multiple sublaminae, with neurites of each neuronal type confined to one or a few layers. This laminar specificity is a major determinant of circuit specificity and circuit function. Using a combination of approaches we show that RGCs targeting IPL sublamina 1 and 3a express the adhesion molecule cadherin 4 (Cdh4). Using calcium imaging and iterative immunostaining, we classified Cdh4-RGCs into 9 types that each encode unique aspects of dark visual stimuli. Cdh4 loss selectively disrupted the layer- targeting of these RGCs, reduced their synaptic inputs from interneurons, and severely altered their visual responses. Overexpression of Cdh4 in other retinal neurons directed their neurites to s1-3a through homophilic interactions. Taken together, these results demonstrate that Cdh4 is a novel layer targeting system for nearly a third of all RGC.

neuroscience↗

bioRxiv2022

Cilium proteomics reveals Numb as a positive regulator of the Hedgehog signaling pathway

The transduction of Hedgehog (Hh) signaling relies on the primary cilium, a cell surface organelle serving as a signaling hub for the cell. Using proximity labeling and quantitative proteomics, we identified Numb as a new ciliary protein that positively regulates Hh signaling. Numb localizes to the ciliary pocket and acts as an endocytic adaptor to incorporate Ptch1 into clathrin-coated vesicles, thereby promoting Ptch1 exit from the cilium, a key step in Hh signaling activation. Numb loss hampers Sonic Hedgehog (Shh)-induced Ptch1 departure from the cilium, resulting in reduced activation of Hh signaling. Numb loss in spinal neural progenitors reduces Shh-induced differentiation into Nkx2.2-positive progenitors, a process reliant on high Hh signaling activity. Genetic ablation of Numb in the developing cerebellum impaired the proliferation of granule cell precursors, a Hh-dependent process, resulting in reduced cerebellar size. This study highlights Numb as a critical regulator of Ptch1 levels in the cilium during Hh signal activation and demonstrates the key role of ciliary pocket-mediated endocytosis in modulating the transduction of cell signaling.

cell biology↗

bioRxiv2022

Pten regulates endocytic trafficking of cell adhesion and signaling molecules to pattern the retina

The retina is an exquisitely patterned tissue, with neuronal somata positioned at regular intervals to completely sample the visual field. Cholinergic amacrine cells are spectacular exemplars of precision, distributing in two radial layers and tangentially, forming regular mosaics. Here, we investigated how the intracellular phosphatase Pten and the cell adhesion molecule Dscam cooperate to regulate amacrine cell patterning. Using double mutants to test epistasis, we found that Pten and Dscam function in parallel pathways to regulate amacrine cell positioning. Mechanistically, Pten regulates endocytic remodeling of cell adhesion molecules (Dscam, Megf10, Fat3), which are aberrantly redistributed in Pten conditional-knock-out (cKO) amacrine cells. Furthermore, extracellular vesicles derived from multivesicular endosomes have altered proteomes in PtencKO retinas. Consequently, Wnt signaling is elevated in PtencKO retinal amacrine cells, the pharmacological disruption of which phenocopies PtencKO patterning defects. Pten thus controls endocytic trafficking of critical cell adhesion/signaling molecules to control amacrine cell spacing. HIGHLIGHTSO_LIPten and Dscam act in parallel pathways to regulate amacrine cell spacing C_LIO_LIEndocytic remodeling of cell adhesion molecules is perturbed in PtencKO retinas C_LIO_LIExtracellular vesicle content is altered in PtencKO retinas C_LIO_LIPerturbation of Wnt signaling phenocopies defects in amacrine cell positioning C_LI eTOC BLURBPatterns in nature range from stereotyped distributions of colored patches on butterfly wings to precise neuronal spacing in the nervous system. Waddington proposed that built-in constraints canalize developmental patterns. Touahri et al. identified Pten-mediated endocytic trafficking of cell adhesion/signaling molecules as a novel constraint measure controlling retinal amacrine cell patterning.

neuroscience↗

bioRxiv2022

Pou3f1 orchestrates a gene regulatory network controlling contralateral retinogeniculate projections

The balance of contralateral and ipsilateral retinogeniculate projections is critical for the establishment of binocular vision, but the transcriptional programs regulating this process remain ill-defined. In this study, we show that the Pou class homeobox protein POU3F1 is selectively expressed in developing mouse contralateral retinal ganglion cells (cRGCs). Inactivation of Pou3f1 increases the number of ipsilateral RGCs produced, leading to abnormal ipsilateral to contralateral projection ratio at the optic chiasm, whereas expression of Pou3f1 in retinal progenitors increases the production of cRGCs. Using Cut&Run and RNA sequencing in wildtype and Pou3f1 mouse knockout retinas, we demonstrate that Pou3f1 is necessary for the establishment of a cRGC gene regulatory network through activation and repression of several known contralateral and ipsilateral determinants, respectively. Finally, we report that POU3F1 is sufficient to induce production of RGC-like cells sending projections to the optic nerve, even in late-stage retinal progenitors not normally competent to generate RGCs. This work uncovers POU3F1 as a master regulator of the cRGC transcriptional program and opens new possibilities for optic nerve regenerative therapies.

developmental biology↗

bioRxiv2021

Ikaros family proteins regulate developmental windows in the mouse retina through convergent and divergent transcriptional programs

Temporal identity factors regulate the competence of neural progenitors to generate specific cell types in a time-dependent manner, but how they operate remains poorly defined. In the developing mouse retina, the Ikaros zinc finger transcription factor Ikzf1 regulates the production of early-born cell types, except cone photoreceptors. In this study we show that Ikzf4, another Ikaros family protein, cooperates with Ikzf1 to control cone photoreceptor production during early stages of retinal development, whereas at late stages, when Ikzf1 is no longer expressed in progenitors, Ikzf4 is instead required for Muller glia production. Using CUT&RUN sequencing, we find that both Ikzf1 and Ikzf4 generally bind to the same genes involved in cone development and other early-born fates, but at different cis-regulatory elements. In late-stage progenitors, Ikzf4 re-localizes to bind target genes involved in Muller glia development and regulate their expression. Specifically, we show that Ikzf4 maintains Hes1 expression in differentiating cells using two Ikzf GGAA binding sites at the Hes1 promoter, thereby favouring Muller glia fate commitment. These results uncover a combinatorial role for Ikaros family members in nervous system development and provide mechanistic insights on how they temporally regulate cell fate output.

developmental biology↗

bioRxiv2021

Numb reduces Tau levels and prevents neurodegeneration in mouse models of tauopathy in an isoform-specific manner

Accumulation of the microtubule-associated protein Tau is linked to neuronal cell death in tauopathies, but how exactly intraneuronal Tau levels are regulated in health and disease remains unclear. Here we identify the trafficking adaptor protein Numb as an essential regulator of Tau homeostasis. Conditional inactivation of Numb in retinal ganglion cells (RGCs) increases monomeric and oligomeric Tau levels, leading to axonal blebbing followed by neuronal cell loss in aged mice. Moreover, in a mouse model of tauopathy, inactivation of Numb in RGCs and spinal motoneurons accelerates neurodegeneration, and leads to precocious hindlimb paralysis. Conversely, overexpression of the long isoform of Numb (Numb-72), but not other isoforms, decreases intracellular Tau levels by promoting the extracellular release of monomeric Tau, and AAV-mediated delivery of Numb-72 in RGCs in vivo prevents neurodegeneration in two different mouse models of tauopathy. Taken together, these results uncover Numb as a modulator of intracellular Tau levels and identify Numb-72 as a novel therapeutic factor for tauopathies.

neuroscience↗

bioRxiv2021

Direct neuronal reprogramming by temporal identity factors

Temporal identity factors are sufficient to reprogram developmental competence of neural progenitors, but whether they could also reprogram the identity of fully differentiated cells is unknown. To address this question, we designed a conditional gene expression system combined with genetic lineage tracing that allows rapid screening of potential reprogramming factors in the mouse retina. Using this assay, we report that co-expression of the early temporal identity transcription factor Ikzf1, together with Ikzf4, another Ikaros family member, is sufficient to directly convert adult Muller glial cells into neuron-like cells in vivo, without inducing a proliferative progenitor state. scRNA-seq analysis shows that the reprogrammed cells share some transcriptional signatures with both cone photoreceptors and bipolar cells. Furthermore, we show that co-expression of Ikzf1 and Ikzf4 can reprogram mouse embryonic fibroblasts to induced neurons by remodeling chromatin and promoting a neuronal gene expression program. This work uncovers general neuronal reprogramming properties for temporal identity factors in differentiated cells, opening new opportunities for cell therapy development.

neuroscience↗

bioRxiv2021

Light-mediated planar polarization of cone photoreceptorcilia contributes to visual acuity in mammals

The coordinated spatial arrangement of organelles within a tissue plane, generally referred to as Planar Cell Polarity (PCP), is critical for various processes ranging from organogenesis to sensory detection. Mechanistically, planar cell polarity is typically set-up by gradients of morphogens and their receptors, but whether non-molecular cues, akin to phototropism in plants, might play a part in setting up PCP in animals remains unknown. Here we report that the basal body of newborn photoreceptor cells in the mouse retina is centrally positioned, but then moves laterally around the first post-natal week, thereby generating cell-intrinsic asymmetry. During the second postnatal week, when eyes open, the basal bodies of cone photoreceptor cilia, but not rods, become coordinated across the tissue plane to face the center of the retina. Mechanistically, we show that light is required during a critical window in development, triggering a non-canonical cascade whereby cone transducin interacts with the G- protein signaling modulator protein 2 (GPSM2), which is in turn necessary for cone PCP. This work uncovers a non-canonical PCP pathway initiated by light.

cell biology↗

bioRxiv2020

A Casz1 - NuRD complex regulates temporal identity transitions in neural progenitors

Neural progenitor cells alter their output over developmental time to generate different types of neurons and glia in the correct sequences and proportions. A number of temporal identity factors that control transitions in progenitor competence have been identified, but the molecular mechanisms underlying their function remain unclear. Here, we asked how the transcription factor Casz1, the mammalian orthologue of Drosophila castor, regulates competence during retinal neurogenesis. 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 other temporal identity factors have been found to interact with the NuRD complex in other contexts, we propose that these factors might act through a common biochemical process to regulate neurogenesis.

developmental biology↗