Biology subjects

Morales, J. E.

Publications and source records attributed to Morales, J. E..

5 recordsLinked to original sources

bioRxiv2026

The Endothelial Cell-Expressed Prion Protein Prnd/Doppel Promotes Neovascularization and Long-term Recovery after Ischemic Stroke

Ischemic stroke remains a leading cause of mortality and long-term disability, yet therapeutic options for promoting recovery remain severely limited. Here, we investigate the role of Prnd/Doppel, a prion family member, in stroke pathophysiology and recovery. Using middle cerebral artery occlusion (MCAO) in mice genetically null for Prnd (KO), inducibly overexpressing Prnd in endothelial cells (ECs), or wild-type (WT) controls, we assessed outcomes through infarct volume measurements, behavioral analysis, and immunohistochemical evaluation of vascular integrity and inflammation. While acute infarct volumes at 24 hours were comparable between WT and KO mice, striking differences emerged during recovery: KO mice exhibited significantly impaired functional outcomes at both 14 and 30 days post-MCAO, accompanied by disorganized cerebrovascular architecture, increased brain atrophy, and elevated CD68-positive inflammatory infiltration by day 30. Conversely, endothelial-specific Prnd overexpression, though not affecting acute outcomes, markedly enhanced tight junction protein expression at day 7, promoted angiogenesis, and improved long-term neuronal survival in the ischemic territory. These findings establish Prnd as a critical mediator of post-stroke vascular remodeling and functional recovery, distinguishing it from acute neuroprotective mechanisms. Our results identify Prnd as a promising therapeutic target for enhancing organized neovascularization and promoting sustained functional recovery following ischemic stroke, with potential applications to other neurological disorders characterized by cerebrovascular dysfunction.

neuroscience↗

bioRxiv2025

GlialCAM Cytoplasmic Signaling in Oligodendrocytes and Astrocytes is Essential for White Matter Homeostasis in the Brain

Glial cell adhesion molecule (GlialCAM) is an astrocyte- and oligodendrocyte-expressed transmembrane protein with two extracellular IgG-like domains and a cytoplasmic tail with putative signaling functions. While numerous studies have explored functions for the GlialCAM IgG-like domains in brain development and physiology, functions for its cytoplasmic signaling tail remain largely unknown. Therefore, we developed a mutant mouse model that expresses a truncated GlialCAM construct (GlialCAM {Delta}CT) that contains intact extracellular and transmembrane domains but lacks the cytoplasmic tail. Deletion of the GlialCAM cytoplasmic domain in glial cells of the brain results in vacuolization within white matter regions without disrupting neurovascular barrier integrity. Consequently, mutant mice exhibited selective deficits in motor coordination, muscular strength, and memory. Single cell transcriptome sequencing identifies GlialCAM-dependent defects in ECM remodeling pathways in white matter tracts. In situ spatial profiling revealed robust activation of astrocytes and microglia in the mutant brain. Proteomic analysis identified GlialCAM cytoplasmic tail interactors with links to MAPK signaling and cytoskeletal regulatory networks. These data reveal important functions for the GlialCAM cytoplasmic tail in homeostasis of white matter tracts in the adult murine brain. The GlialCAM {Delta}CT model may also be useful for studying the pathogenesis and possible treatment of neurological diseases linked to white matter degeneration.

neuroscience↗

bioRxiv2025

Single Cell RNA Sequencing and Spatial Profiling Identify Mechanisms of Neonatal Brain Hemorrhage Development and Resolution

Precise control of cell-cell communication networks within brain neurovascular units (NVUs) promotes normal tissue physiology, and dysregulation of these networks can lead to pathologies including intracerebral hemorrhage (ICH). The cellular and molecular mechanisms underlying ICH development and subsequent tissue repair processes remain poorly understood. Here we employed quantitative single cell RNA sequencing coupled with spatial in situ gene expression profiling to characterize NVU signaling pathways associated with ICH in neonatal mouse brain tissue. The initial stages of ICH pathogenesis are characterized by downregulation of extracellular matrix (ECM)-associated signaling factors (Adamtsl2, Htra3, and Lama4) that functionally connect to canonical TGF{beta} activation and signaling in vascular endothelial cells. Conversely, the progressive resolution of ICH involves upregulation of neuroinflammatory signaling networks (Gas6 and Axl) alongside activation of iron metabolism pathway components (Hmox1, Cp, and Slc40a1) in astrocytes and microglial cells. Integrated computational modeling identifies additional ligand-receptor signaling networks between perivascular glial cells and endothelial cells during both ICH pathogenesis and resolution. Collectively, these findings illuminate the molecular signaling networks that promote NVU maturation and provide novel mechanistic insights into the pathways controlling ICH pathogenesis and repair.

developmental biology↗

bioRxiv2024

In Situ Single-Cell Spatial Profiling of Matrisome Gene Expression in Glioblastoma

The human brain contains a rich milieu of extracellular matrix (ECM) components that are often dysregulated in pathologies including the malignant cancer glioblastoma (GBM). Here, we have used in situ single-cell spatial transcriptomic platforms to map the expression patterns of nearly 400 ECM genes in normal brain and GBM samples. Our analysis identifies at least four different GBM cell populations with unique ECM expression profiles that show spatial enrichment in distinct intratumor regions. Spatial mapping also demonstrates largely non-overlapping expression signatures of various ECM components in GBM stromal cell types, particularly in vascular endothelial cells and reactive microglia/macrophages. Comparisons of GBM (IDH1 wild type) versus lower-grade II and III astrocytoma samples (IDH1 R132H) identifies differential expression of key ECM components, including elevated levels of select ECM glycoproteins (IGFBP2 and MGP) and ECM-affiliated proteins (ANXA1 and ANXA2). In addition, we detect spatially enriched expression of COL8A1 (collagen), LUM (proteoglycan), and POSTN (ECM glycoprotein) in perivascular stromal cells in GBM but not in lower grade tumors. Computational analysis of putative ligand-receptor interactions reveals novel ECM communication networks between cancer cells and stromal components, particularly in regions of GBM microvascular proliferation and pseudopalisading necrosis. In summary, this comprehensive spatial map provides new insights into microenvironmental control of GBM initiation and progression and identifies potential therapeutic targets in the ECM.

cancer biology↗

bioRxiv2022

HepaCAM Suppresses Glioblastoma Stem Cell Invasion in the Brain

Glioblastoma (GBM) is a malignant brain cancer that contains sub-populations of highly invasive tumor cells that drive progression and recurrence after surgery and radiochemotherapy. The exact mechanisms that enable GBM cells to disperse from the main tumor mass and navigate throughout the brain microenvironment remain largely unknown. As a result, there is a lack of effective strategies to block cancer cell invasive growth in primary and recurrent GBM. Here we report that hepatocyte cell adhesion molecule (hepaCAM), which is normally expressed in perivascular astrocytes, plays central roles in controlling the invasive growth features of GBM cells. Genetically targeting HEPACAM induces a transition from GBM cell proliferation/self-renewal to invasion. Increased invasion is due, in part, to an activation of focal adhesion signaling pathways and enhanced GBM cell adhesion to the extracellular matrix (ECM) in the brain microenvironment. Transcriptional profiling of GBM cells reveals various HEPACAM-regulated genes with links to polarity and invasion. Collectively, these data show that hepaCAM balances ECM adhesion and signaling pathways to control cancer cell proliferation versus invasion in the brain parenchyma. Targeting select components of the hepaCAM pathway may be an effective way to block tumor progression and recurrence in patients with GBM.

cancer biology↗