Browsing by Author "Sabbagh, Ubadah"

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    A cell–ECM mechanism for connecting the ipsilateral eye to the brain
    Su, Jianmin; Sabbagh, Ubadah; Liang, Yanping; Olejníková, Lucie; Dixon, Karen G.; Russell, Ashley L.; Chen, Jiang; Pan, Yuchin Albert; Triplett, Jason W.; Fox, Michael A. (National Academy of Sciences, 2021-10-15)
    Information about features in the visual world is parsed by circuits in the retina and is then transmitted to the brain by distinct subtypes of retinal ganglion cells (RGCs). Axons from RGC subtypes are stratified in retinorecipient brain nuclei, such as the superior colliculus (SC), to provide a segregated relay of parallel and feature-specific visual streams. Here, we sought to identify the molecular mechanisms that direct the stereotyped laminar targeting of these axons. We focused on ipsilateral-projecting subtypes of RGCs (ipsiRGCs) whose axons target a deep SC sublamina. We identified an extracellular glycoprotein, Nephronectin (NPNT), whose expression is restricted to this ipsiRGC-targeted sublamina. SC-derived NPNT and integrin receptors expressed by ipsiRGCs are both required for the targeting of ipsiRGC axons to the deep sublamina of SC. Thus, a cell–extracellular matrix (ECM) recognition mechanism specifies precise laminar targeting of ipsiRGC axons and the assembly of eye-specific parallel visual pathways.
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    The development, cytoarchitecture, and circuitry of the ventral lateral geniculate nucleus
    Sabbagh, Ubadah (Virginia Tech, 2021-05-28)
    In the visual system, retinal axons convey visual information from the outside world to dozens of distinct retinorecipient brain regions. In rodents, two major areas that are densely innervated by this retinal input are the dorsal lateral geniculate nucleus (dLGN) and ventral lateral geniculate nucleus (vLGN), both of which reside in the thalamus. The dLGN is well-studied and known to be important for classical image‐forming vision. The vLGN, on the other hand, is associated with non‐image‐forming vision and its neurochemistry, cytoarchitecture, and retinothalamic connectivity all remain unresolved, raising fundamental questions of its role within the visual system. Here, we sought to shed light on these important questions by studying the cellular and extracellular landscape of the vLGN and map its connectivity with the retina. Using bulk RNA sequencing and proteomics, we identified extracellular matrix proteins that form two molecularly distinct types of perineuronal nets in two major laminae of vLGN: the retinorecipient external vLGN (vLGNe) and the non‐retinorecipient internal vLGN. Using in situ hybridization, immunohistochemistry, electrophysiology, and genetic reporter lines, we found that vLGNe and vLGNi are also composed of diverse subtypes of neurons. In vLGNe, we discovered at least six transcriptionally distinct subtypes of inhibitory neurons that are distributed into distinct adjacent sublaminae. Using trans‐synaptic viral tracing and ex vivo electrophysiology, we found that cells in each these sublaminae receive direct inputs from retina. Lastly, by genetically removing visual input, we found that the organization of these sublaminae is dramatically disrupted, suggesting a crucial role for sensory input in the cytoarchitectural maintenance of the vLGN. Taken together, these results not only identify novel subtypes of vLGN cells, but they also point to new means of organizing visual information into parallel pathways – by anatomically creating distinct sensory channels. This subtype-specific organization may be key to understanding how the vLGN receives, processes, and transmits light‐derived signals in the subcortical visual system.
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    Diverse GABAergic neurons organize into subtype-specific sublaminae in the ventral lateral geniculate nucleus
    Sabbagh, Ubadah; Govindaiah, Gubbi; Somaiya, Rachana D.; Ha, Ryan V.; Wei, Jessica C.; Guido, William; Fox, Michael A. (Wiley, 2020-05-19)
    In the visual system, retinal axons convey visual information from the outside world to dozens of distinct retinorecipient brain regions and organize that information at several levels, including either at the level of retinal afferents, cytoarchitecture of intrinsic retinorecipient neurons, or a combination of the two. Two major retinorecipient nuclei which are densely innervated by retinal axons are the dorsal lateral geniculate nucleus, which is important for classical image-forming vision, and ventral LGN (vLGN), which is associated with non-image-forming vision. The neurochemistry, cytoarchitecture, and retinothalamic connectivity in vLGN remain unresolved, raising fundamental questions of how it receives and processes visual information. To shed light on these important questions, used in situ hybridization, immunohistochemistry, and genetic reporter lines to identify and characterize novel neuronal cell types in mouse vLGN. Not only were a high percentage of these cells GABAergic, we discovered transcriptomically distinct GABAergic cell types reside in the two major laminae of vLGN, the retinorecipient, external vLGN (vLGNe) and the non-retinorecipient, internal vLGN (vLGNi). Furthermore, within vLGNe, we identified transcriptionally distinct subtypes of GABAergic cells that are distributed into four adjacent sublaminae. Using trans-synaptic viral tracing and in vitro electrophysiology, we found cells in each these vLGNe sublaminae receive monosynaptic inputs from retina. These results not only identify novel subtypes of GABAergic cells in vLGN, they suggest the subtype-specific laminar distribution of retinorecipient cells in vLGNe may be important for receiving, processing, and transmitting light-derived signals in parallel channels of the subcortical visual system.
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    Region- and Cell-Specific Expression of Transmembrane Collagens in Mouse Brain
    Monavarfeshani, Aboozar; Kill, Courtney N.; Sabbagh, Ubadah; Su, Jianmin; Fox, Michael A. (Frontiers, 2017-08-30)
    Unconventional collagens are nonfribrillar proteins that not only contribute to the structure of extracellular matrices but exhibit unique bio-activities. Although roles for unconventional collagens have been well-established in the development and function of non-neural tissues, only recently have studies identified roles for these proteins in brain development, and more specifically, in the formation and refinement of synaptic connections between neurons. Still, our understanding of the full cohort of unconventional collagens that are generated in the mammalian brain remains unclear. Here, we sought to address this gap by assessing the expression of transmembrane collagens (i.e., collagens XIII, XVII, XXIII and XXV) in mouse brain. Using quantitative PCR and in situ hybridization (ISH), we demonstrate both region- and cell-specific expression of these unique collagens in the developing brain. For the two most highly expressed transmembrane collagens (i.e., collagen XXIII and XXV), we demonstrate that they are expressed by select subsets of neurons in different parts of the brain. For example, collagen XXIII is selectively expressed by excitatory neurons in the mitral/tufted cell layer of the accessory olfactory bulb (AOB) and by cells in the inner nuclear layer (INL) of the retina. On the other hand, collagen XXV, which is more broadly expressed, is generated by subsets of excitatory neurons in the dorsal thalamus and midbrain and by inhibitory neurons in the retina, ventral thalamus and telencephalon. Not only is col25a1 expression present in retina, it appears specifically enriched in retino-recipient nuclei within the brain (including the suprachiasmatic nucleus (SCN), lateral geniculate complex, olivary pretectal nucleus (OPN) and superior colliculus). Taken together, the distinct region- and cell-specific expression patterns of transmembrane collagens suggest that this family of unconventional collagens may play unique, yet-to-be identified roles in brain development and function.
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    Retinal inputs signal astrocytes to recruit interneurons into visual thalamus
    Su, Jianmin; Charalambakis, Naomi E.; Sabbagh, Ubadah; Somaiya, Rachana D.; Monavarfeshani, Aboozar; Guido, William; Fox, Michael A. (2020-02-04)
    Inhibitory interneurons comprise a fraction of the total neurons in the visual thalamus but are essential for sharpening receptive field properties and improving contrast-gain of retinogeniculate transmission. During early development, these interneurons undergo long-range migration from germinal zones, a process regulated by the innervation of the visual thalamus by retinal ganglion cells. Here, using transcriptomic approaches, we identified a motogenic cue, fibroblast growth factor 15 (FGF15), whose expression in the visual thalamus is regulated by retinal input. Targeted deletion of functional FGF15 in mice led to a reduction in thalamic GABAergic interneurons similar to that observed in the absence of retinal input. This loss may be attributed, at least in part, to misrouting of interneurons into nonvisual thalamic nuclei. Unexpectedly, expression analysis revealed that FGF15 is generated by thalamic astrocytes and not retino-recipient neurons. Thus, these data show that retinal inputs signal through astrocytes to direct the long-range recruitment of interneurons into the visual thalamus.