Friday, November 04, 2005

Neural Wiring   posted by Fly @ 11/04/2005 04:36:00 PM

Scientists Crack Code for Motor Neuron Wiring

“Dasen's functional analysis revealed a Hox coding hierarchy. “He found that the Hox proteins involved in pool identity are different from those involved in column identity,” said Jessell. “So from these data, the idea began to emerge that within the chromosomal Hox clusters, some Hox proteins are dedicated to broad aspects of motor neuron differentiation, and others to finer aspects of diversification. Ultimately, what crystallized from these experiments was a code — an organized relationship between Hox proteins, their chromosomal organization, and the differentiation and connectivity of motor neuron pools,” he said.

Jessell said this code appears to govern three levels of motor neuron organization: the columnar organization that ensures that motor neurons project into the limb; the divisional organization of motor neurons that determines whether motor neurons project to muscles in the dorsal or ventral halves of the limb; and finally, the motor neuron pool identity that governs the muscle target of each set of motor neurons. In a key set of experiments, Dasen showed that alterations in Hox expression patterns in specific neurons resulted in changes in motor neuron identity, and in their connectivity to muscle targets.”

“The studies also raise the possibility that the combinatorial code contains additional information, beyond the regulation of motor neuron wiring. “This is still conjecture, but the sheer number of Hox proteins, and their capacity to direct neuronal differentiation, suggests that they may also impart identity to the interneurons that enable them to connect selectively with motor neurons. And, aspects of the code could also give identity to sensory neurons, enabling their connections with motor neurons,” said Jessell. Deciphering the entire Hox code could provide crucial insights into the organization of the complex circuitry that the spinal cord uses to control muscle action.”

(Warning: leaving the realm of science and entering Fly speculations…or fantasy. Erroneous info ahead.)

We have two pieces of the puzzle. The Hox proteins provide a label (or trigger) that tells a cell what it is. We also have gene chips and protein chips that can tell us what genes are turned-on and what proteins are being built. So what occurs in between?

I believe there is DNA whose expression is triggered by the Hox proteins and that DNA controls the cell specific gene expression. I think of this DNA as scripting code. The scripting DNA wouldn’t directly code for the common structural, enzymatic, or signaling proteins.

The scripting DNA would be short in comparison to most protein-coding DNA. A mutation in this DNA would only affect specific cell types so evolution of the scripting DNA could lead to optimal gene expression for different tissues. (Whereas a mutation in most protein-coding genes would affect many cell types.) Since the scripting DNA would be short, mutations would be infrequent so less selection would be needed to maintain genome quality. Scripts would be built on top of other scripts. Low-level common scripts should be highly conserved.

The scripting DNA should have a distinctive nucleotide signature. Unlike protein-coding DNA, every nucleotide could be significant. The script DNA would be copied into RNA that would then fold into specific functional shapes. So the RNA functional shape patterns should be represented in the DNA sequence patterns. (Some scripting DNA could act through regulatory proteins. My guess is that nature doesn’t care if “machine code”, “C code”, or “scripting code” is mixed together into a complex jumble.)

My guess is that most of the design information for an animal is in this scripting DNA. Protein-coding genes tell how to build blocks and scripting DNA tells how to put the blocks together to form an animal.

What would be scripted?

Consider brain wiring. How is one neural cluster connected to another by a nerve bundle? First each cluster of neurons must travel to the proper location in the brain. The body has many fluid pathways. There is the blood circulatory system, the lymph system, and slow fluid flow from the blood system through the tissues to the lymph system. (In the earliest embryonic stages, diffusion would play a major role. As the embryo grows I’d expect fluid flow to become more important.) Thus the entire body is a drainage system with directional fluid flow. These fluid flows serve to pass chemical signals from one place to another. So chemical gradients could be used to guide cells to their destination. Each neuron type would need its own address (Hox proteins?) and instructions that convert that address into directional movements (DNA scripts?).

Once in place, the neuron sends out chemical signals. Somehow two neural clusters recognize specific signals and axons grow to connect the regions. Some of the guiding is constrained by body architecture. The axons are going to flow along the body fluid paths carrying the proper chemical signal. But occasionally the axon is going to have go against the main fluid flow and follow the chemical gradient generated by the target neurons. So DNA has code for the target neurons releasing specific signals and for the source neuron axons to respond to those signals and grow toward those targets.

There may be many unique chemical messengers and many unique receptors. (Protein-coding genes with alternate splicing could generate the unique types. A DNA script could be translated into RNA that interacts with intron RNA to control mRNA splicing.) Or there might be many ways for a cell to interpret chemical signals. Suppose a neuron axon is tracking three chemical signals. The neuron might track signals with a special ratio of those three types. A DNA script that controlled the ratio of cell membrane receptors for those signals might determine what signals caused the largest response. Or perhaps a neuron recognizes a time varying pattern of chemical messengers. There are many ways that signals can be sent and recognized. All of the ways require DNA information.

Clearly the wiring isn’t determined down to the individual neurons. But there are many nerves and many specialized brain modules. Thus the information needed to wire the human body must be extensive.

Also consider instinctive behavior. Every instinct is embedded in neural structures. So there must be DNA that codes for specific neural patterns that underlie specific instincts. So even more information is needed to build that brain.

Why do I think that scripting DNA exists?

I don’t believe there is enough information in the protein-coding DNA to build a human being. There is twice as much non-coding DNA conserved in the genome as there is protein-coding DNA. Since the scripting DNA would tend to be shorter than the protein-coding DNA it could hold much more design information. Scripts could be built based on top of lower-level scripts making the information storage more efficient. Our cells contain elaborate molecular machinery for manipulating DNA and RNA. So there are many mechanisms by which DNA/RNA might regulate gene expression or protein production without requiring a protein intermediary.