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Huang Lab

Huang Lab

Zhen Huang, Ph.D.
Zhen Huang, Ph.D.

Cortical neuron migration and laminar assembly

My lab is interested in several aspects of the development of the cerebral cortex. We are interested in how the different levels of organization in the cortex, from global to cellular and synaptic organization and from neural to vascular patterning, arise during normal development and how they may be affected in and contribute to brain neural and vascular diseases.

To investigate how the exquisite layer organization of the cortex arises, we focus on the question of how the generation and migration of neurons and glia are regulated. We employ mouse genetics approaches and use tissue specific gene knockout technology to answer this question. Among the genes of interest to us is a gene involved in G protein coupled receptor (GPCR) signaling. We have found that mutation in this gene, ric-8a, which encodes a guanine nucleotide exchange factor (GEF) for heterotrimeric G proteins, results in cobblestone lissencephaly-like malformation in the cerebral cortex as well as lobule formation defects in the cerebellum. One of our goals is to use this mutation as an entry point to gain new insights into mechanisms by which cell-cell communication coordinates the complex process of brain development.

The normal embryonic (E16.5) cortex contains a densely packed cortical plate underneath a cell-sparse marginal zone (Nuclear staining in green). A pial basement membrane (Laminin staining in red) enwraps the cortex on the surface. In ric-8a mutants, ectopic neurons are found at the pial surface, in association with breaks in the basement membrane, similar to phenotypes in type II (cobblestone) lissencephaly in humans.

Blood vessel development in the brain

To understand how blood vessel development in the brain is regulated, we focus on interactions between neural and vascular cells. Specifically, we have found that radial glia, neural progenitor cells in the developing brain, play an unexpected in regulating the stabilization of nascent blood vessels. In the absence of radial glia, newly formed blood vessels in the cortex become destabilized and eventually undergo regression. This provides a unique model to determine how new blood vessels in the brain are stabilized. One of our goals is to determine the identity of the signal(s) involved as well as the vascular genes regulated by radial glia. We are also interested in whether and how these genes may be involved in and contribute to brain neurovascular diseases.

Blood vessels (outlined in green) form a stereotypic network in the neonatal mouse cortex in normal control animals. In mutants where radial glial neural progenitors are ablated, many vessels undergo regression and are lost (see details in Ma et al. 2012 PLoS Biology).

Transducin Partners Outside the Phototransduction Pathway
Srivastava D, Yadav RP, Inamdar SM, Huang Z, Sokolov M, Boyd K, Artemyev NO.
Front Cell Neurosci. 2020 Oct 14;14:589494. doi: 10.3389/fncel.2020.589494. eCollection 2020.
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Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention
Santhosh D, Sherman J, Chowdhury S, Huang Z.
Dis Model Mech. 2019 Nov 11;12(11):dmm041228. doi: 10.1242/dmm.041228.
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A Brain-Region-Specific Neural Pathway Regulating Germinal Matrix Angiogenesis
Ma S, Santhosh D, Kumar T P, Huang Z.
Dev Cell. 2017 May 22;41(4):366-381.e4. doi: 10.1016/j.devcel.2017.04.014.
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A Tie2-driven BAC-TRAP transgenic line for in vivo endothelial gene profiling
Santhosh D, Huang Z.
Genesis. 2016 Mar;54(3):136-45. doi: 10.1002/dvg.22923. Epub 2016 Feb 15.
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Regulation of the nascent brain vascular network by neural progenitors
Santhosh D, Huang Z.
Mech Dev. 2015 Nov;138 Pt 1:37-42. doi: 10.1016/j.mod.2015.06.005. Epub 2015 Jul 7.
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B Lymphocyte-Specific Loss of Ric-8A Results in a Gα Protein Deficit and Severe Humoral Immunodeficiency
Boularan C, Hwang IY, Kamenyeva O, Park C, Harrison K, Huang Z, Kehrl JH.
J Immunol. 2015 Sep 1;195(5):2090-102. doi: 10.4049/jimmunol.1500523. Epub 2015 Jul 31.
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Neural Regulation of CNS Angiogenesis During Development
Ma S, Huang Z.
Front Biol (Beijing). 2015 Feb;10(1):61-73. doi: 10.1007/s11515-014-1331-y.
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Radial glial neural progenitors regulate nascent brain vascular network stabilization via inhibition of Wnt signaling
Ma S, Kwon HJ, Johng H, Zang K, Huang Z.
PLoS Biol. 2013;11(1):e1001469. doi: 10.1371/journal.pbio.1001469. Epub 2013 Jan 22.
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A functional requirement for astroglia in promoting blood vessel development in the early postnatal brain
Ma S, Kwon HJ, Huang Z.
PLoS One. 2012;7(10):e48001. doi: 10.1371/journal.pone.0048001. Epub 2012 Oct 24.
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Ric-8a, a guanine nucleotide exchange factor for heterotrimeric G proteins, regulates bergmann glia-basement membrane adhesion during cerebellar foliation
Ma S, Kwon HJ, Huang Z.
J Neurosci. 2012 Oct 24;32(43):14979-93. doi: 10.1523/JNEUROSCI.1282-12.2012.
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Harnessing a novel Ab40 anti-inflammatory pathway for AD intervention
Sponsor: ICTR Pilot Funds
Award: ICTR-UWHC RD 14
09/01/2020 - 01/31/2022

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