Graduate Studies Faculty
Sijun Zhu, MD, PhD
- Associate Professor of Neuroscience and Physiology
Research Programs and Affiliations
- Biomedical Sciences Program
- Neuroscience Program
- Neuroscience and Physiology
Education & Fellowships
- Postdoctoral Fellow: University of California at San Francisco, 2012
- PhD: University of Illinois at Urbana-Champaign, 2005, Developmental Neurobiology
Genetic mechanisms of Drosophila neural stem cell self-renewal and specification.
Our lab is interested in elucidating genetic mechanisms that control the generation of brain complexity and the formation of brain tumors. The increased brain complexity is believed to be responsible for higher intellectual ability in humans. Generating brain complexity requires the maintenance of neural stem cells (NSCs) and the production of intermediate neural progenitor cells (INPs), transient amplification of which is critical for boosting the number of neurons and glia generated from NSCs. However, aberrant proliferation of NSCs and INPs can lead to brain tumor formation. In our lab, we use a particular type of NSCs called type II neuroblasts (NBs) in Drosophila larval brains as a model to dissect genetic mechanisms that control the maintenance of NSCs and the generation of INPs. Drosophila type II NBs remarkably resemble mammalian NSCs. They can not only maintain their own population through self-renewal throughout the larval development but also produce large amount of neurons by generating transient amplifying INPs (Figure 1A-A'). Furthermore, type II NB lineages are extremely susceptible to tumorigenesis. Thus, type II NB lineages provide an excellent model for studying the generation of brain complexity and the formation of brain tumors. Our research goals are to uncover the gene regulatory network that control NSC self-renewal and INP production and to understand how dysregulation of the gene regulatory network may lead to brain tumor formation using various genetic, molecular and cell biological, and confocal imaging approaches. Currently, we are focusing on the following three specific projects.
(1) Investigate how type II NBs are specified and maintained. Our previous studies reveal that specification of type II NBs requires the Ets family transcription factor Pointed P1 (PntP1). Meanwhile, maintaining the identity and self-renewal of type II NBs but not the type I NBs, which produce terminal dividing progenitor cells called ganglion mother cells (GMCs) but not INPs, critically relies on the Notch signaling pathway. We will elucidate detailed molecular mechanisms underlying the PntP1-mediated specification of type II NBs and the Notch-mediated maintenance of type II NB identity and self-renewal.
(2) Investigate how INPs avoid premature differentiation and cell cycle exit. A major function of INPs is to amplify neuronal output from NSCs through transient proliferation. Therefore, avoiding differentiation and cell cycle exit is critically important for the function of INPs. Our recent studies show that PntP1 and the Sp family transcription factor Buttonhead (Btd) act together to prevent the premature differentiation of INPs. Loss of either PntP1 or Btd leads to elimination of INPs (e.g. Figure 1B-B'). We will investigate how PntP1 and Btd act cooperative to prevent the premature differentiation of INPs.
(3) Investigate how INPs avoid dedifferentiation and tumorigenic overproliferation. INPs are prone to dedifferentiation and tumorigenic overproliferation in the absence of tumor suppressors (e.g. Figure 1C-C'). We recently found that PntP1 is also required to prevent the dedifferentiation of INPs in addition to preventing the premature differentiation. We want to understand how PntP1 prevents the dedifferentiation of INPs and what is the functional relationship between PntP1 and other tumor suppressors in preventing the dedifferentiation of INPs.
Figure 1. (A-A') A normal type II NB lineage labeled with GFP (A) and schematic diagrams of the lineage and its neurogenesis pattern (A'). (B-') A type II NB lineage with premature differentiation of INPs. (C-C') A type II NB lineage with defects in INP differentiation.
Li X, Chen R, Zhu S. bHLH-O proteins balance the self-renewal and differentiation of Drosophila neural stem cells by regulating Earmuff expression. Dev Biol. 2017 Nov 15;431(2):239-251. doi: 10.1016/j.ydbio.2017.09.011. Epub 2017 Sep 9.PMID:28899667
Xie Y, Li X, Deng X, Hou Y, O'Hara K, Urso A, Peng Y, Chen L, Zhu S. The Ets protein Pointed prevents both premature differentiation and dedifferentiation of Drosophila intermediate neural progenitors. Development. 2016 Sep 1;143(17):3109-18. doi: 10.1242/dev.137281. Epub 2016 Aug 10. PMID:27510969
Li X, Xie Y, Zhu S. Notch maintains Drosophila type II neuroblasts by suppressing expression of the Fez transcription factor Earmuff. Development. 2016 Jul 15;143(14):2511-21. doi: 10.1242/dev.136184. Epub 2016 May 5.PMID:27151950
Xie Y, Li X, Zhang X, Mei S, Li H, Urso A, Zhu S. The Drosophila Sp8 transcription factor Buttonhead prevents premature differentiation of intermediate neural progenitors. Elife. 2014 Oct 6;3. doi: 10.7554/eLife.03596.PMID:25285448
Zhu S, Wildonger J, Barshow S, Younger S, Huang Y, Lee T. The bHLH repressor Deadpan regulates the self-renewal and specification of Drosophila larval neural stem cells independently of Notch. PLoS One. 2012;7(10):e46724. doi: 10.1371/journal.pone.0046724. Epub 2012 Oct 8.PMID:23056424
Zhu S, Barshow S, Wildonger J, Jan LY, Jan YN. Ets transcription factor Pointed promotes the generation of intermediate neural progenitors in Drosophila larval brains. Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20615-20. doi: 10.1073/pnas.1118595109. Epub 2011 Dec 5.PMID:22143802
Han C, Wang D, Soba P, Zhu S, Lin X, Jan LY, Jan YN. Integrins regulate repulsion-mediated dendritic patterning of drosophila sensory neurons by restricting dendrites in a 2D space. Neuron. 2012 Jan 12;73(1):64-78. doi: 10.1016/j.neuron.2011.10.036.PMID:22243747
Soba P, Zhu S, Emoto K, Younger S, Yang SJ, Yu HH, Lee T, Jan LY, Jan YN. Drosophila sensory neurons require Dscam for dendritic self-avoidance and proper dendritic field organization. Neuron. 2007 May 3;54(3):403-16.PMID:17481394
Zhu S, Lin S, Kao CF, Awasaki T, Chiang AS, Lee T. Gradients of the Drosophila Chinmo BTB-zinc finger protein govern neuronal temporal identity. Cell. 2006 Oct 20;127(2):409-22.PMID:17055440
Kuo CT, Zhu S, Younger S, Jan LY, Jan YN. Identification of E2/E3 ubiquitinating enzymes and caspase activity regulating Drosophila sensory neuron dendrite pruning. Neuron. 2006 Aug 3;51(3):283-90.PMID:16880123
Zhu S, Perez R, Pan M, Lee T. Requirement of Cul3 for axonal arborization and dendritic elaboration in Drosophila mushroom body neurons. J Neurosci. 2005 Apr 20;25(16):4189-97.PMID:15843622