טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentGrimm Julie
SubjectThe Nuclear Hormone Receptor NHR-25/Ftz-F1 Controls
Dendritic Arborization and Repair after Injury
in Caenorhabditis Elegans
DepartmentDepartment of Biology
Supervisor Professor Benjamin Podbilewicz
Full Thesis textFull thesis text - English Version


Abstract

Proper neuronal branching is essential for functional neuronal systems and misregulated branching can lead to neurodegeneration and disease. Our work seeks to identify genes involved in either normal development or injury response of a neuron and analyze their distinct functions.

Our model neuron, the mechanosensory PVD, is the most arborized neuron in C. elegans and its process of branching is a topic of increasing interest. The PVD serves as a model for developmental branching, injury and neurodegenerative processes all known to involve branch growth and stabilization.  Cell adhesion protein, FMI-1’s mammalian homologs are known to regulate neuronal development and its role in PVD branching was investigated.  FMI-1 appears to have a complex involvement in PVD development and mutant alleles gave variable phenotypes ranging from hyper to hypobranched.

 Work on the PVD has uncovered a systematic response to laser nano surgery: bypass of self-avoidance mechanisms followed by reattachment at or near the site of injury, sprouting and simplification of branches. Failure of PVD reattachment results in degeneration of the distal fragment. 

 NHR-25 (a nuclear hormone receptor) and EFF-1 (epidermal fusion failure 1, a cell-cell fusion protein) have both been implicated in developmental branching and have known roles in epidermal fusion processes.  In response to injury, nhr-25 deficient worms show excess branching at and around the site of injury up to 50 hours post injury, a time when ectopic branching would normally be pruned back. Epistasis analysis unveiled that this function is due to positive regulation of eff-1 by nhr-25.  In normal PVD development, EFF-1 is known to act cell-autonomously to regulate branching and after injury to aid in arbor simplification.  In order to dissect how NHR-25 functions in normal branching and in response to injury tissue specific rescue experiments were designed as well as live imaging of protein dynamics.   By analyzing NHR-25 expression I found that NHR-25 expression is reduced in the hypodermis in response to injury.  Furthermore, our tissue specific rescue of mutant nhr-25 worms demonstrated that some branching phenotypes including post injury branching are controlled via the skin. These results suggest a non-cell autonomous role for some functions of NHR-25. Our finding provides a link between the external and internal neuronal environment and the regenerative ability of the neuron itself.