miR-125b toggles dynamics and structure of dendritic filopodia in developing hippocampal neurons

The wiring of the nervous system is an intricate process of self-organization, of unparalleled complexity in the natural world. To get a sense of the scope of the requirement, imagine all the billions of phones and computers connected by wires to form the internet. Imagine if these wires branch out and divide, avoiding inimical landscapes and waters, to reach the right servers and computers, which turn had to send out wires to meet yet other servers and so on, till you have the internet of today. Now imagine that instead of a few billion computers, you had eighty-six billion neurons. Instead of men laying down the wiring on pre-programmed routes, the wires had to grow on their own. And instead of the lands and seas of Earth, you had to achieve all this in the space of a single human skull. This is the self-organization challenge of the axons and dendrites of the brain. Developing dendrites encounter a variety of stimuli that direct their growth and final architecture. Cellular substrates respond to these stimuli, integrating extrinsic information to direct dendritic growth. Of interest in this process are microRNAs, small noncoding RNAs around 22 nucleotides long, which can reversibly repress local translation in dendrites. By responding to external cues sensed by dendritic filopodia, they participate in the key decision-making processes in developing dendrites: where and how to grow. This study focuses on the role of miR-125b, a brain abundant microRNA, for its role in the dynamics and structure of filopodia in developing dendrites. We inhibited miR- 125b’s activity in cultured hippocampal neurons during the early stages of development as filopodia explore their microenvironment. We show that miR-125b function is critical for maintaining the structural features of filopodia, and that inhibiting its function changes the distribution of the type of protrusions emerging from dendritic shafts. Inhibiting miR-125b increases dendritic expression and localization of the GluN2A subunit of the NMDA receptor, and we show that dendritic GluN2A is correlated with maintaining filopodial morphology. Using Spatial Light Interference Microscopy (SLIM), we show that miR-125b function contributes to maintaining the dynamicity of filopodia. We propose that miR-125b is critical in maintaining the filopodial phenotype early in dendrite development, thus contributing to dendritogenesis and spinogenesis. Through its regulation of GluN2A, miR-125b shapes neuronal response to the synaptotrophic factor glutamate. These high-resolution analyses reveal fresh insights into the process by which neurons integrate multiple external signals to establish the correct connections. Such insights are critical to understanding the implicated role of miR125b in various neurological disorders like Fragile X Syndrome and Alzheimer’s disease.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Cell and Developmental Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2020

Author dc:creator

• Iyer, Rajashekar

Contributors dc:contributor

• Gillette, Martha U.
• Ceman, Stephanie S.
• Brieher, William M.
• Sweedler, Jonathan V.

• Filopodia, MicroRNA

Statement dc:rights

• Copyright 2018 Rajashekar Iyer

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/101315

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/101315