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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC Santa Cruz Electronic Theses and Dissertations (2016)

The highly complex and specialized functions of the mammalian cortex rely on precise temporal development and organization of the diverse neuronal cell types found within by multiple cellular processes. A complete understanding of the molecular mechanisms regulating these events remains elusive. Given that many genes and cellular processes are conserved from mouse to human, I utilize the mammalian cerebral cortex in Mus musculus, as a model system for studying cortical development. Here, I present results from a detailed characterization of the transcription factor Myocyte Enhancing Factor 2C (Mef2c) during postnatal mouse cortical development. Mef2c, considered an upper layer gene, is expressed in all 6 layers of the cerebral cortex including a subpopulation of corticofugal projection neurons. Given its expression pattern in the cortex and previously identified functions in myocyte and CNS development, we hypothesized that Mef2c was a key regulator of neocortical development. Cell type specific and temporal expression analysis revealed that MEF2C is expressed in subcerebral projection neurons throughout corticogenesis. Using a conditional loss-of-function approach, we compared cortical development of control (Mef2ccontrol) and conditional knock out (Mef2ccKO) mice to identify the role of Mef2c. Results revealed that MEF2C expression pattern is similar to that of SATB2 and is in part positively regulated by Satb2. We showed that MEF2C is expressed in subcerebral neurons and is partially required to promote and maintain the identity of these neurons into early postnatal ages. Furthermore, we showed that MEF2C is required for axonal outgrowth of subcerebral projection neurons, such that Mef2ccKO brains displayed a significant loss of axon projections to subcerebral targets compared to Mef2ccontrol. Additionally, callosal neuron distribution analysis suggested that MEF2C acts to inhibit a callosal cell identity in deep layer neurons. Together, these data indicate the broad yet critical roles for Mef2c during the organization and development of the mouse cerebral cortex.

    Cover page: Transcriptional Regulation Of Subcerebral Cortical Projection Neurons At Multiple Steps Of Mammalian Cortical Development
    • Article
    • Peer Reviewed
    LBL Publications (2022)
    Costimulatory receptors such as glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) play key roles in regulating the effector functions of T cells. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect, which may be due to suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (GITR-L) that induces PD-1-dependent and FcγR-independent GITR clustering, resulting in enhanced activation, proliferation and memory differentiation of primed antigen-specific GITR+PD-1+ T cells. The anti-PD-1-GITR-L bispecific is a PD-1-directed GITR-L construct that demonstrated dose-dependent, immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models, with a dose-dependent correlation between target saturation and Ki67 and TIGIT upregulation on memory T cells. Anti-PD-1-GITR-L thus represents a bispecific approach to directing GITR agonism for cancer immunotherapy.
      Cover page: An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy.
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