The morphology of axons and dendrites shapes the connectivity and function of neuronal circuits; and dysmorphic axons and dendrites are a common feature of neurodevelopmental disorders. To establish cell-type-specific morphologies, developing neurites need to (1) grow towards and branch in the right places (i.e. neurite targeting), (2) elaborate arbors with distinct branching patterns and geometries (i.e. neurite shape), and (3) occupy appropriate territories (i.e. neurite size). How axons and dendrites grow to an exact size, how arbor size regulates connectivity, and how it influences specific circuit computations is not well understood. In preliminary studies, we identified four cell adhesion molecules (CAMs; Amigo1, Amigo2, netrin-G1, and NGL1) that regulate dendrite and axon size of neurons in two circuits of the retina: the direction selective (DS) circuit, which extracts motion information in the inner retina, and the rod bipolar pathway, which transmits dim-light-signals from the outer to the inner retina. Starburst cells have radially symmetric arbors that overlap extensively among neighbors and express Amigo2. The central two thirds of each arbor receive input and the peripheral third provides output. Inhibitory input from starburst cells is critical for DS responses of ganglion cells. Neurite size of starburst cells is increased in Amigo2 knockout (Amigo2-/-) mice, while functional compartmentalization is maintained.
In Aim 1, we will analyze the molecular mechanisms of Amigo2?s actions, test its influence on neurite morphology and connectivity, DS circuit function, and image stabilizing head and eye movements. At the first stage of the rod bipolar pathway, horizontal cell axons mediate lateral inhibition among rods, which provide input to rod bipolar dendrites. Horizontal cells express Amigo1. In Amigo1-/- mice, horizontal cell axons and rod bipolar dendrites are both reduced in size.
In Aim 2, we will characterize the signaling mechanism of Amigo1, explore territory matching between synaptic partners, analyze effects on connectivity and measure light sensitivity along the rod bipolar pathway, and in behavioral responses. At the second stage of the rod bipolar pathway, netrin-G1-expressing rod bipolar axons synapse onto NGL1-expressing AII cells. Rod bipolar axon size is reduced in netrin- G1-/- and NGL1-/- mice, suggesting that retrograde signals of trans-synaptic netrin-G1/NGL1 complexes regulates axon growth.
In Aim 3, we will explore whether forward signals control AII arbor size. We will determine how netrin-G1/NGL1 complexes affect the number, ultrastructure and function of synapses between rod bipolar and AII cells, and assess their influences on light responses along the rod bipolar pathway and on the ability of mice to detect dim light flashes. Together these studies will provide insights into the molecular mechanisms that control axon and dendrite size in the retina, reveal how neurite size regulates connectivity, and how it shapes specific circuit computations and influences visually guided behaviors.

Public Health Relevance

This proposal aims to elucidate molecular mechanisms that control axon and dendrite size in the retina. A better understanding of these mechanisms could provide important insights into neurodevelopmental disorders, which frequently involve disruptions of neuronal morphogenesis. In addition, knowledge about signals that govern axon and dendrite development, may prove useful in guiding the integration of neuronal replacements, which, particularly in the retina, are promising candidates for restoring function lost by degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY027411-01
Application #
9217364
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Greenwell, Thomas
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$381,250
Indirect Cost
$131,250
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130