Xinyu Zhao’s laboratory focuses on understanding the molecular mechanisms that regulate neural stem cells and neuronal development, with the goal to develop better treatment for human brain disorders.
Her lab is particularly interested in neural stem cells in the central nervous system of postnatal and adult mammals. Zhao’s research shows that these neural stem cells have significant roles in normal brain functions, such as learning and memory and brain’s response to injuries.
Zhao uses genetic modified mice and primary neural stem cells as model systems and a combination of molecular, cellular, imaging, and behavioral techniques to investigate the molecular mechanisms that regulate postnatal neuronal development and its implication in human neurodevelopmental disorders, such as Rett Syndrome, autism, and fragile X syndrome.
- Novel Method for Enhancing BDNF Protein Expression
Although the mutation of X-linked MECP2 gene is known to cause Rett syndrome (RTT), effective therapeutic treatment for this devastating disorder is lacking. Extensive evidence has identified BDNF as a downstream effector of MeCP2. Reduced expression of BDNF protein in the brain is characteristic of RTT and enhancing BDNF can alleviate neurological symptoms associated with MeCP2 deficiency. However, an effective method for elevating BDNF protein levels in the brain is still lacking. We have found that MeCP2-deficiency leads to both up and down regulation of noncoding small RNAs (nsRNAs) in neural stem cells and neurons and some of the microRNAs are predicted to target BDNF mRNA and potentially regulate BDNF protein translation. Here, we propose a one-year pilot project to explore a novel therapeutic idea. Our hypothesis is that some MeCP2-regualted nsRNAs can modulate BDNF protein translation and manipulation of these nsRNAs may be used as therapeutic methods for treating RTT. To achieve the goal of this project, we propose the following specific aims (1) to establish in vitro screening systems for identifying nsRNAs that promote BDNF translation; (2) using these systems to identify nsRNAs and nsRNA inhibitors that can promote BDNF protein translation; and (3) to determine whether manipulation of nsRNAs can promote BDNF protein expression in the brain with MeCP2 deficiency. If this pilot project indicates positive outcome, further translational investigations will sprout from this effort, leading to potential new treatments for RTT.
- Role of Small RNAs in Neurogenesis
Neurogenesis is defined as generation and maturation of new neurons. Postnatal neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. Deciphering these regulatory mechanisms represents a step towards understanding the development and plasticity of postnatal mammalian brains, and realizing the therapeutic potential of neural stem/progenitor cells (NSCs). Epigenetic mechanisms, including DNA methylation and histone modification, are known to play significant roles in the modulation of stem cell proliferation and differentiation. Methyl-CpG binding proteins, including MBD1 and MeCP2, are central players in epigenetic regulation, and can translate DNA methylation into gene expression changes. MBD1 deficiency has been reported in sporadic human cancers, consistent with its role in cellular growth control. Despite its ubiquitous expression pattern, we found that MBD1 deficiency in mice results largely in brain-associated phenotypes during the postnatal period, including impaired adult neurogenesis and related behavioral deficits such as defective hippocampus-dependent learning and susceptibility to anxiety and depression. Recently, MBD1 mutations were found in a subset of autistic patients and were correlated with more severe phenotypes. The precise role of MBD1 in postnatal neuronal development and molecular pathway mediating its effect is not fully clear. During the past three-year funding period, we discovered that MBD1 regulates the expression of a number of miRNAs and some of these miRNAs exhibit an important regulatory role in neurogenesis. For example, miR-184 promotes proliferation and represses differentiation of adult NSCs by repressing the expression of Numblike (Nbl), a regulator of Notch signaling. The complete picture of this regulatory network is still lacking. In addition to its role in NSC proliferation and neuronal differentiation, we discovered that MBD1 had important roles in maturation of new neurons. Some of MBD1-regulated miRNAs have been implicated in neuronal maturation. Taken together, these discoveries serve as the basis of this project which is aimed towards a better understanding of the epigenetic mechanisms controlling multiple stages of postnatal neurogenesis. We will test the hypothesis that MBD1 regulation of miRNAs and their subsequent downstream targets is critical for postnatal neurogenesis.