1. Biointelligence Laboratory, Seoul National University
Ch 5. The patterning of neural connections 5.7 ~ 5.9 Adaptive Cooperative Systems, Martin Beckerman, 1997.
Summarized by
Kim, S.-J.
Biointelligence Laboratory, Seoul National University

2. (C) 2009, SNU Biointelligence Lab, http://bi.snu.ac.kr/
Contents
5.7 Growth cone guidance and neurite outgrowth
5.7.1 Chemoattractants
5.7.2 Chemorepulsants
5.7.3 Cell adhesion molecules
5.8 Signal transduction and integration
5.8.1 Dynamics regulation of cell surface receptors
5.8.2 Intracellular calcium signaling
5.8.3 G-Proteins
5.9 Dynamics
(C) 2009, SNU Biointelligence Lab, 

3. Growth cone guidance and neurite outgrowth
Neural growth cone
It is responsible for the sensing and navigational activities of developing axons (nerve fibers).
Neurite outgrowth
Neurite elongation:
the elaboration of new neurite length
It depends on microtubules concentrated in the neurite shaft.
Growth cone motility:
the sampling and forward movements of the growth cone and their filopodia and lamellipodia
It depends on cytoskeletal actin and associated proteins.
(C) 2009, SNU Biointelligence Lab, 

4. Growth cone guidance and neurite outgrowth
Actin filaments, actin-associated proteins and cell surface molecules are distributed on growth cones and on their filopodia and lamellipodia.
Cell Surface molecules include integrins, L1, NCAM, and N-cadherin.
Integrin and L1: high concentrations on DRG (dorsal root ganglion) growth cone filopodia
NCAM and N-cadherin: more widly distributed on growth cones, but NCAM is mostly absent from filopodia
The growth cone (green) on the left is an example of a “filopodial” growth cone, while the one on the right is a “lamellipodial” growth cone. Typically, growth cones have both structures, but with varying sizes and numbers of each.
(C) 2009, SNU Biointelligence Lab, 

5. Growth cone guidance and neurite outgrowth
Local mechanical, chemical, and electrical interactions all play important roles in producing the precise connections that characterize the nervous system.
Important constituents of the plasma membrane of growth cones include G-proteins and voltage-dependent calcium channels.
G-proteins and calcium channels serve several important signaling and integrating functions.
We will discuss signal transduction mechanisms, concentrating on the regulation of neurite outgrowth and growth cone motility by intracellular calcium, and on the strong cooperativity promoted by G-proteins.
(C) 2009, SNU Biointelligence Lab, 

6. (C) 2009, SNU Biointelligence Lab, http://bi.snu.ac.kr/
Chemoattractants
The search for chemotropic factors that began with Ramon y Cajal’s hypothesis that chemotropic agents guide neurite outgrowth has produced both chemoattractants and chemorepulsants.
Chemoattractants
Chemoattractants are inorganic or organic substances possessing chemotaxis inducer effect in motile cells.
Netrins function as circumferential chemoattractants emanating from the floor plate at the ventral midline of the developing spinal cord (Serafini et al. and Kennedy et al.).
These molecules provide guidance signals for the growth cones of the commissural neurons whose axons extend toward and across the floor plate.
(C) 2009, SNU Biointelligence Lab, 

7. (C) 2009, SNU Biointelligence Lab, http://bi.snu.ac.kr/
Chemorepulsants
Chemorepulsants (chemorepellents)
Inorganic or organic substances possessing chemotaxis modulator, negative effect in motile cells.
Luo et al. have discovered that a secreted protein , collapsin, extracted from adult chick brain membrane has the ability induce the collapse and paralysis of growth cones.
The brief overview of chemoattractants and chemorepulsants
Baier and Bonhoeffer et al.: The ability of growth cones to read gradient of surface-associated information
Goodman: some guidance molecules may be attractive for some growth cones and repulsive for others, depending on the receptor.
(C) 2009, SNU Biointelligence Lab, 

8. Cell adhesion molecules
Cell Adhesion Molecules (CAMs) are proteins located on the cell surface involved with the extracellular matrix (ECM).
Three classes of cell adhesion promoting receptors are colocated on growth cones
integrins: a family of heterophilic CAMs
NCAM (neural cell-adhesion molecule): members of the immunoglobulin gene super-family
N-cadherin: a family of homophilic CAMs
Integrins promote growth cone motility and neurite outgrowth over ECM.
Most of the ligands bound by integrins, such as laminin, are extracellular matrix proteins that are involved in cell adhesion.
NCAM and N-cadherin support these activities but differ from integrins in that they mostly operate through homophilic binding mechanisms.
(C) 2009, SNU Biointelligence Lab, 

9. Cell adhesion molecules
Most of our knowledge about NCAM and N-cadherin function in cell adhesion and signal transduction comes from studies of neurite outgrowth in cultured neurons.
Homophilic cell–cell adhesion in trans between neurons and NCAM-expressing feeder cells induces clustering of NCAM on neurons, which, in turn, results in the activation of the fibroblast growth factor receptor (FGFR)
(C) 2009, SNU Biointelligence Lab, 

10. Dynamic regulation and integration
Transmembrane signaling follows receptor-ligand interactions and all classes of cell surface receptors are dynamically regulated on neurons.
Integrins operate dynamically in more than one way and in concert with other receptors.
Integrins interact directly with cytoskeletal proteins and they activate second-messenger pathways.
Integrin activation can induce increase in Ca2+ signaling and integrin signaling pathways may be integrated with other receptor pathways through G-protein-coupled receptors.
(C) 2009, SNU Biointelligence Lab, 

11. Intracellular calcium signaling
Intracellular calcium regulates neurite outgrowth and growth cone motility.
The calcium hypothesis is a statement that if the level of calcium either falls below an optimal range or rises above it, motility and outgrowth are inhibited.
This idea is that excitatory neurotransmitters lead to alterations in membrane potential that increase in intercellular calcium levels that serves to inhibit further motility and outgrowth.
Electrical activity can either increase or decrease motility and outgrowth dependent on the calcium levels present at the time of stimulation.
The electrical activity influences the pattern of connectivity.
voltage-gated calcium channels
Neurotransmitters and action potentials each cause changes in the intracellular calcium levels and the integrated overall level will determine whether to continue to grow or to stop.
(C) 2009, SNU Biointelligence Lab, 

12. (C) 2009, SNU Biointelligence Lab, http://bi.snu.ac.kr/
G-proteins
G-proteins, short for guanine nucleotide-binding proteins, are a family of proteins involved in second messenger cascades.
G proteins are important signal transducing molecules in cells.
G-protein-linked receptors are membrane-spanning proteins that respond to extracellular signaling agents such as hormones and neurotransmitters.
The heterotrimeric G-proteins, to which these receptors are linked, are loosely bound to the inner surface of the plasma membrane.
Their three distinct subunits are termed α, β and γ.
They are activated in response to a conformation change in the G-protein-coupled receptor, exchange GDP (guanosine diphosphate) for GTP (guanosine triphosphate) , and dissociate to activate other proteins in the signal transduction pathway.
(C) 2009, SNU Biointelligence Lab, 

13. (C) 2009, SNU Biointelligence Lab, http://bi.snu.ac.kr/
G-proteins
The protein encoded by this gene has been termed a 'growth' or 'plasticity' protein because it is expressed at high levels in neuronal growth cones during development
Transduction and integration. Schematic view of the role of G0 in the integration of extracellular and intercellular signals in growth cones. (strittmatter and Fishman)
(C) 2009, SNU Biointelligence Lab, 

14. (C) 2009, SNU Biointelligence Lab, http://bi.snu.ac.kr/
Dynamics
In the retinotectal projection, we observe that the multiple interactions and cooperativity support the presence of multiple stable states.
The presence of multiple stable states and the order-disorder transitions we have been exploring in an equilibrium dynamics may be regarded as static adaptive properties.
The presence of a variety of stable states over the system parameter ranges, coupled to an ability of the system to alter its parameters as the need arises in response to signaled changes in the internal and external environments, may be viewed as dynamics adaptive properties.
(C) 2009, SNU Biointelligence Lab, 

15. Reorganization in the adult cortex
The central nervous system of the adult retains its adaptive capabilities.
We observe dynamic adaptive changes in adult mammalian receptive fields and topographic organization when we induce injuries and when we modify the character of the input stimuli.
Plastic changes have been found in a variety of primary cortical areas and thalamic nuclei, and they seem to changes in synaptic level through mechanism that are Hebbian (mechanisms of synaptic plasticity).
The changes in synaptic efficiency may be promoted by the dense networks of horizontal connections and by the feedforward and feedback circurity.
(C) 2009, SNU Biointelligence Lab, 

16. Time course of developmental events
In the investigation of the time course of laminar development, Tzonev et al. find that local cell-cell interactions generate a wave of development of neuronal receptive fields that propagates through the nucleus and establishes the two distinct laminar patterns.
(C) 2009, SNU Biointelligence Lab,