Biology subjects

Harwell, C.

Publications and source records attributed to Harwell, C..

7 recordsLinked to original sources

bioRxiv2026

Progenitor Diversity and Architecture of the Human Ganglionic Eminences Shaping the Basal Ganglia

The embryonic medial and lateral ganglionic eminences (MGE, LGE) are the principal sources of most neurons and glia for the basal ganglia. In primates, the MGE has a distinctive cytoarchitecture characterized by doublecortin enriched cellular nests (DENs), yet the architectonic organization underlying DEN formation, the molecular heterogeneity of ganglionic eminence progenitors and their lineage relationships, remain poorly understood. Here, using paired single-nucleus transcriptomics and chromatin accessibility profiling of the three GEs, we identify distinct progenitor populations, delineate their gene regulatory networks, and reconstruct their lineage trajectories. Live imaging reveals a unipolar outer radial glia-like population (GE-oRG) that undergoes mitotic somal translocation. Spatial transcriptomics identifies a distinct CRABP1+/ANGPT2+ domain within the MGE. Integrated spatial and electron microscopy demonstrates a periphery-to-center gradient of differentiation in the MGE. Leveraging DEN-forming MGE organoids derived from PCDH19 knockout human pluripotent stem cell lines, we identify the protocadherin, PCDH19, as a key regulator of DEN formation.

neuroscience↗

bioRxiv2024

Conservation, alteration, and redistribution of mammalian striatal interneurons

Mammalian brains vary in size, structure, and function, but the extent to which evolutionarily novel cell types contribute to this variation remains unresolved1-4. Recent studies suggest there is a primate-specific population of striatal inhibitory interneurons, the TAC3 interneurons5. However, there has not yet been a detailed analysis of the spatial and phylogenetic distribution of this population. Here, we profile single cell gene expression in the developing pig (an ungulate) and ferret (a carnivore), representing 94 million years divergence from primates, and assign newborn inhibitory neurons to initial classes first specified during development6. We find that the initial class of TAC3 interneurons represents an ancestral striatal population that is also deployed towards the cortex in pig and ferret. In adult mouse, we uncover a rare population expressing Tac2, the ortholog of TAC3, in ventromedial striatum, prompting a reexamination of developing mouse striatal interneuron initial classes by targeted enrichment of their precursors. We conclude that the TAC3 interneuron initial class is conserved across Boreoeutherian mammals, with the mouse population representing Th striatal interneurons, a subset of which expresses Tac2. This study suggests that initial classes of telencephalic inhibitory neurons are largely conserved and that during evolution, neuronal types in the mammalian brain change through redistribution and fate refinement, rather than by derivation of novel precursors early in development.

evolutionary biology↗

bioRxiv2024

Multimodal classification of neurons in the lateral septum

The lateral septum (LS) is a ventral forebrain nucleus that modulates complex social and affective behaviors. These behaviors emerge from heterogeneous neuronal populations whose molecular identity and developmental origins remain poorly defined. We profiled the transcriptional identity of mature LS neurons derived from two progenitor lineages distinguished by their embryonic origin and Nkx2.1 expression history, identifying 22 molecularly distinct subtypes. Nkx2.1-lineage neurons are enriched for select cell adhesion and communication molecules; however, subtypes from distinct developmental origins can converge onto similar molecular profiles when residing within the same LS subregion. The graded expression of genes related to synaptic signaling is a primary axis defining the taxonomy of LS neurons. Using transcriptional markers, we labeled non-overlapping neuronal populations and characterized their connectivity, morphology, and electrophysiology. Together, these findings define the extent of LS neuronal diversity and provide a framework for understanding how complex behaviors are regulated by the LS.

neuroscience↗

bioRxiv2023

PRDM16 co-operates with LHX2 to shape the human brain

PRDM16 is a dynamic transcriptional regulator of various stem cell niches, including adipocytic, hematopoietic, cardiac progenitors, and neural stem cells. PRDM16 has been suggested to contribute to 1p36 deletion syndrome, one of the most prevalent subtelomeric microdeletion syndromes. We report a patient with a de novo nonsense mutation in the PRDM16 coding sequence, accompanied by lissencephaly and microcephaly features. Human stem cells were genetically modified to mimic this mutation, generating cortical organoids that exhibited altered cell cycle dynamics. RNA sequencing of cortical organoids at day 32 unveiled changes in cell adhesion and WNT-signaling pathways. ChIP-seq of PRDM16 identified binding sites in postmortem human fetal cortex, indicating the conservation of PRDM16 binding to developmental genes in mice and humans, potentially at enhancer sites. A shared motif between PRDM16 and LHX2 was identified and further examined through comparison with LHX2 ChIP-seq data from mice. These results suggested a collaborative partnership between PRDM16 and LHX2 in regulating a common set of genes and pathways in cortical radial glia cells, possibly via their synergistic involvement in cortical development.

developmental biology↗

bioRxiv2020

Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical circuit assembly

Neuron-glia relationships play a critical role in the regulation of synapse formation and neuronal specification. The cellular and molecular mechanisms by which neurons and astrocytes communicate and coordinate are not well understood. Here we demonstrate that the canonical Sonic hedgehog (Shh) pathway is active in cortical astrocytes, where it acts to coordinate layer-specific synaptic connectivity and functional circuit development. We show that Ptch1 is a Shh receptor that is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of layer-specific astrocyte genes involved in regulating synapse formation and function. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses, moreover, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Together, these results suggest that Shh secreted from deep layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function.

neuroscience↗

bioRxiv2019

Transcriptional regulation of MGE progenitor proliferation by PRDM16 controls cortical GABAergic interneuron production

The mammalian cortex is populated by neurons derived from neural progenitors located throughout the embryonic telencephalon. Excitatory neurons are derived from progenitors located in the dorsal telencephalon, while inhibitory interneurons are generated by ventral telencephalic progenitors. The transcriptional regulator PRDM16 is expressed by radial glia, neural progenitors present in both regions; however, its mechanisms of action are still not fully understood. It is unclear if PRDM16 functions plays a role in neurogenesis in both dorsal and ventral progenitor lineages, and if so, whether it does so by regulating common or unique networks of genes. Here, we show that Prdm16 expression in MGE progenitors is required for maintaining their proliferative capacity and for the production of proper numbers of pallial GABAergic interneurons. PRDM16 binds to cis-regulatory elements and represses the expression of region-specific neuronal differentiation genes, thereby controlling the timing of neuronal maturation. Our results highlight the importance of PRDM16 for the development of both excitatory and inhibitory cortical circuits. We demonstrate the existence of convergent developmental gene expression programs regulated by PRDM16, which utilize both common and region-specific sets of genes in the cortex and the MGE to control the proliferative capacity of neural progenitors, ensuring the generation of correct numbers of cortical neurons.

neuroscience↗

bioRxiv2019

Sonic hedgehog signaling in astrocytes mediates cell-type-specific synaptic organization

Astrocytes have emerged as integral partners with neurons in regulating synapse formation and function, but the mechanisms that mediate these interactions are not well understood. Here, we show that Sonic hedgehog (Shh) signaling between neurons and astrocytes is required for establishing structural organization and remodeling of cortical synapses in a cell type-specific manner. In the postnatal cortex, Shh signaling is active in a subpopulation of mature astrocytes localized primarily in deep cortical layers. Selective disruption of Shh signaling in astrocytes produces a dramatic increase in synapse number specifically on layer V apical dendrites that emerges during adolescence and persists into adulthood. Dynamic turnover of dendritic spines is impaired in mutant mice and is accompanied by an increase in neuronal excitability and a reduction of the glial-specific, inward-rectifying K+ channel Kir4.1. These data identify a critical role for Shh signaling in astrocyte-mediated modulation of neuronal activity required for sculpting synapses.

neuroscience↗