During neural development, billions of neurons differentiate, migrate, send out axons, and synapse onto their targets in a precisely choreographed sequence. Acquisition of neuronal polarity by progenitor cells or newborn neurons drives many early morphogenetic processes including the exit of these cells from germinal niches, migration initiation to a final laminar position or axon-dendrite specification during neural circuit formation. Despite the discovery of polarity pathways acting concurrently with differentiation, it's unclear how neurons traverse complex polarity transitions or how neuronal progenitors control the onset of polarization during development. Identifying such mechanisms can advance our understanding of neuronal migration disorders as well as diseases like pediatric cancers where germinal zone (GZ) exit is compromised. My laboratory uses the Partitioning Defective or Pard, cell polarity signaling complex as a model to understand the molecular and cellular mechanisms controlling cerebellar granule neuron (CGN) neuronal differentiation, polarization, and migration in the developing cerebellum. Our previous work examining the cell biological underpinning of CGN development illustrates that Pard complex signaling regulates multiple events that are coincident with CGN differentiation including GZ exit, radial migration initiation, neuronal adhesion to migration substrates and the cadence of nucleokinesis. In the previous funding cycle of this grant, we investigated how Pard complex activity is regulated during CGN differentiation. We identified a novel mechanism where the mRNA expression of the Pard6? and Pard3 Pard complex components is excluded from granule neuron progenitors (GNPs) by the Zeb1 transcriptional repressor. Necessity-sufficiency and epistasis analysis using ex vivo cell biological approaches show that Zeb1 controls GZ exit, neurite extension and radial migration initiation in a Pard6? and Pard3 dependent fashion. We will expand on our preliminary studies by examining how Zeb1 controls GZ occupancy and is regulated by extrinsic GZ conditions with these Aims:
Aim1. Determine how Zeb1 and Pard6? control GNP GZ occupancy through Itg?1 adhesion.
Aim2 : Determine how the EGLN1-VHL-Hif1? pathway controls CGN differentiation and polarization via Zeb1. These studies will address two important questions in the developing brain: 1) What are the adhesive mechanisms that maintain GZ occupancy of progenitors cells and how they are attenuated as polarization proceeds during differentiation? Investigating this question will provide insight into the GZ exit defects that frequently accompany pediatric cancer. 2) How do environmental conditions like oxygen tension control the maturation of progenitor cells and differentiating neurons? Investigating this question will provide insight into how defective oxygen homeostasis associated with pre-term birth or perinatal hypoxia perturbs neural development.

Public Health Relevance

Duringneuraldevelopment,thematurationofnervecellsdrivesfundamentalcellularprocessesthatassemble neuronalcircuitry.Thisproposalstudiesthemechanismsgoverningthecellbiologyofneuronaldifferentiationand howenvironmentalcueslikeoxygentensionfacilitate maturation.Theimagingtoolsandconceptualadvances developedbythisproposalwillnotonlyexpandour knowledgeofneuraldevelopmentbutcouldleadtonew diagnosticsandtreatmentsforneurodevelopmental disorders, suchaspediatriccancersordevelopmentaldefects associatedwithpre-termbirth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS066936-09
Application #
9970545
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
2011-09-01
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Ong, Taren; Solecki, David J (2017) Seven in Absentia E3 Ubiquitin Ligases: Central Regulators of Neural Cell Fate and Neuronal Polarity. Front Cell Neurosci 11:322
Trivedi, Niraj; Stabley, Daniel R; Cain, Blake et al. (2017) Drebrin-mediated microtubule-actomyosin coupling steers cerebellar granule neuron nucleokinesis and migration pathway selection. Nat Commun 8:14484
Singh, Shalini; Howell, Danielle; Trivedi, Niraj et al. (2016) Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition. Elife 5:
Singh, Shalini; Solecki, David J (2015) Polarity transitions during neurogenesis and germinal zone exit in the developing central nervous system. Front Cell Neurosci 9:62
Ramahi, Joseph S; Solecki, David J (2014) The PAR polarity complex and cerebellar granule neuron migration. Adv Exp Med Biol 800:113-31
Trivedi, Niraj; Ramahi, Joseph S; Karakaya, Mahmut et al. (2014) Leading-process actomyosin coordinates organelle positioning and adhesion receptor dynamics in radially migrating cerebellar granule neurons. Neural Dev 9:26
Famulski, Jakub K; Solecki, David J (2013) New spin on an old transition: epithelial parallels in neuronal adhesion control. Trends Neurosci 36:163-73
Solecki, David J (2012) Sticky situations: recent advances in control of cell adhesion during neuronal migration. Curr Opin Neurobiol 22:791-8