Why study development?

Most of you will have children of your own. You should have some understanding of the process of development. Most importantly you should understand why environmental insults such as alcohol, drugs, smoking, and industrial pollutants can have such dramatic affects on embryonic development.

Abortion is a moral and not a scientific issue, but if you're going to argue your moral case either for or against abortion you should have your scientific facts corrects.

In the future you will be asked to decide upon profound issues of reproductive cloning, therapeutic cloning, and biological engineering. What type of cloning should be allowed? Should we allow biologically engineered humans? What sort of changes should be allowed and what should be banned?
Should there be a basic human right to biological engineering of the germ line for improvement of the "race"?

I study development for all these reasons and more. I think understanding development, and in particular the development of the brain is the most exciting scientific field today.


Introduction to Developmental Biology

Development of complex multicellular organism consisting of hundreds of different tissues, thousands of different specialized cell types and trillions of cells all arose from single cell; the fertilized egg.

Who would believe you if you told them you had a tiny fantastically self organizing nucleus that could be added to a vat of sand, trace metals, plastic, and a modest source of energy and 9 months later there’s a supercomputer.

And yet that’s exactly what happens. The human body is orders of magnitude more complex than anything we can engineer, and its an engineer’s dream: low cost, self organizing, self replicating

We speak of development as being epigenetic. A linear strand a DNA in the zygote encodes proteins--it does not encode body parts. There is no place in the genome that encodes a hand. There is no point to point correspondence between the genome and the organism. The DNA exists in the complex environment of the embryo. The fertilized egg, even excluding the nucleus, is a very information rich environment, information that regulates the zygotic DNA. In fact, you may be surprised to find that the zygotic nucleus has very little to do with the first stages of embryogenesis in many organisms.

Development assures two main functions: self organization and self replication, both intertwined functions.

1. The generation of cell number (growth)
2. The generation of cell diversity (differentiation)
3. The organization of differentiated cells into tissues and organs (morphogenesis)

Major features of animal development are as follows:

GAMETOGENESIS
Sexually mature adult: male gamete- haploid sperm (generally small with densely packed DNA and motile.
female gamete- haploid egg or oocyte (generally among the largest cells of the body, non motile)
Why sex? Why go through haploid-diploid state? It is an almost universal feature of complex multicellular animals.

Sexual reproductive cycle involves an alternation of haploid generations of cells with a single set of chromosomes, and diploid generations of cells with a double set of chromosomes.

Cycle of haploidy, cell fusion, diploidy----meiosis (recombination) reduction division----haploid cells with new combinations of genes.

In many multicellular animals the diploid phase is complex and long while the haploid phase is simple.

germ line -----haploid gametes, sperm and egg
somatic cells----diploid, all the rest of the cells of body

Benefits of Sex:
1. capture new useful mutations
2. phenotypically diverse offspring improves chances of survival in unpredictably variable environment

FERTILIZATION
Mechanisms for assuring species specificity--only the proper sperm is able to fertilize an egg, eg., sea urchin sperm (and not fish!) recognize, penetrate, and fertilize a sea urchin egg.

Fertilization joins the genetic material from sperm and egg to produce fertilized egg or zygote and activates the program of embryogenesis.

Initial development is dependent on maternal factors put into the egg during oogenesis. Egg is only cell of the body that can produce another organism; the most specialized and unspecialized cell.

Hunt for source of initial asymmetries----a/p and d/v axis.


CLEAVAGE
A series of stereotyped relatively rapid mitotic divisions whereby the large volume of the egg cytoplasm is parceled into many smaller cells: cell division without cell growth. The cleavage stage cells of the embryo are called BLASTOMERES and the ball of blastomeres is first termed a morula and later when a fluid filled cavity develops (the Blastocoel) is termed the BLASTULA (epithelium, tight junctions, pumping of Na to create blastocoel)
Initial state: egg is a very complex and highly organized structure of lipid, carbohydrate, protein, and nucleic acids.

Stereotyped cleavage patterns may parcel out different cytoplasms and membranes (that contain different information molecules) into different blastomeres.

Midblastula transition: embryo switches its dependence from maternal to zygotic transcripts

QUESTIONS WE CAN BEGIN TO ASK
How is cell fate determined? Intrinsic vs. extrinsic determination of cell fate
A Fate map is a picture of adult tissues, organs, and/or body parts drawn on a late blastula stage embryo that indicates what blastomeres will give rise to which body parts and is dependent on the stereotype patterns of cell divisions and cell movements that occurs during development. .
The opposite extremes are a strict lineage model versus the cell position as the determining factor. EXAMPLE: Generate million cells---identity determined solely by cell lineage or conversely by cell position


Deterministic vs regulative development: deterministic is lineage based and predicts that removing a cell will result in a specific and predictable deficit, while regulative suggests extrinsic determination and plasticity in determining cell fate, and predicts that removing a specific cell will be no different than removing any other cell and will produce little or no deficit in the resulting embryo.

What do we mean by cell determination and differentiation? Lets leave cell determination for a while and just talk about differentiation. A differentiated cell is distinguished from other cells by the unique pattern of genes that it expresses, generally related to its specific specialized function, eg., muscle cells --actin and myosin for movement, nerve cells --voltage gated sodium channels for propagation of the action potential and transmission of information.

Each Mammalian cell has genetic instructions for about 25,000 genes, yet each cell type expresses a small subset of these, about 10,000, most of which are shared among all cells. About 10% specify unique differentiated functions.

Determination defines when a cell is committed to a particular differentiated fate, generally long before a differentiated phenotype is visible.

Molecular mechanisms? All cells have basically the same DNA.
1. Transcriptional: DNA---RNA
2. Translational: RNA----Protein
3. Post translational regulation: Protein modifications
4. Intracellular signaling that regulates transcriptional, translational, and posttranslational regulatory pathways.

GASTRULATION
The rapid pace of cell division seen during cleavage slows and the blastomeres begin to move relative to one another in a stereotype pattern. Gastrulation refers to the extensive rearrangement of cells that transforms the single layered epithelial bound cavity (blastocoel) into a three layered structure. The three germ layers consist of the outer ectoderm (epidermis and nervous system), middle mesoderm (bones and muscles), and the inner endoderm (gut and associated organs).

Anterior to Posterior (AP) and Dorsal to Ventral (DV) axis become apparent

First of classic INDUCTIVE events. The induction of the ectodermally derived neural tube by the underlying mesoderm.

Induction refers to an event in which one cell or group of cells influences how another cell or group of cells behaves (differentiates)
Dorsal ectoderm that is normally fated to become nervous tissue does not differentiate properly if the nearby mesoderm is removed.

What is the molecular nature of the inductive signal? How do the receiving cells respond to alter their differentiation?

Pattern formation: the establishment of an ordered array of cells from cells which appear less ordered. Normally associate pattern formation with the development of limbs, lung, brain, and so on that is organogenesis. In fact the process of development is a continual increase in apparent complexity and pattern.
We will be especially interested in studying how the anterior-posterior and dorsal-ventral patterns arise in development long before any classical organogenesis begins.

ORGANOGENESIS
Through a process that often begins with induction, cells multiply, migrate, differentiate, and organize themselves into organs. Here is where the differentiated phenotypes really become most apparent and the cell-cell interactions mediated by cell surface ligands and receptors most obviously important.

We will discuss the development of the eye, limbs, and CNS (neuronal pathfinding and target recognition) because they are the most extensively studied examples.

BIRTH
Birth of most organisms marks the transition from development in the controlled environment within the egg case or parent to the uncontrolled cruel world

GROWTH AND MATURATION
Requires interaction of the animal with the environment to find food for growth. Development is now modified by interactions with the particular environment the animal finds itself in.

Animal often learns to adapt to its environment by altering its behavior. Learning and memory, healing and more extreme regeneration, are continuing developmental processes.

REPRODUCTION
Those more successful survive to complete the cycle and leave more progeny. The basis of evolution is the survival of the more fit animals to reproduce. Sexual (and even asexual) reproduction leads to genetic variation and differing developmental processes that result in individuals with differing phenotypes.

What is the relationship between development and evolution?

Most of you could probably tell me apart from a chicken, but I doubt if any of you could tell the difference between a 2 day old chick embryo and a 1 month human embryo. We share common ancestors, thus we share common developmental mechanisms.

DEATH
Programmed part of developmental process or explained by evolutionary selection?