Cell-Cell Communication

Cell Death, Juxtacrine Signalling, Extracellular Matrix & Gap Junctions

Apoptosis

• Programmed cell death - normal part of development

• Nematode C. elegans - precisely 1090 somatic cells - 131 of these cells die

– 302 nerve cells come from 405 cells - 103 die

• In general all cells are programmed to die unless told not to

Apoptosis

• In humans up to 10¹¹ cells die each day in a normal adult - they are replaced by other cells

– The mass of cells we lose each year is close to our entire body weight

– We make about 3 times more neurons than we are born with

• Apoptosis removes unneeded structures - sculpts complex organs

Apoptosis in Nematodes

• Proteins coded by Ced-3 and Ced-4 genes essential for apoptosis

• In cells that did not undergo apoptosis - the above genes were were turned off by the products of Ced-9 gene

• CED-4 protein is a protease activating factor for CED-3 - a protease that initiates the destruction of the cell

Apoptosis Pathways

Blocking Apoptosis

Juxtacrine Signalling

• Proteins from the inducing cell interact with receptor proteins on adjacent responding cells

• Three types

– 1. Protein on one cell binds to its receptor on the adjacent cell

– 2. A receptor on one cell binds to its ligand on the extracellular matrix secreted by another cell

– 3. The signal is transmitted directly from the cytoplasm of one cell through conduits into the cytoplasm of an adjacent cell

The Notch Pathway

• A ligand (Delta, Jagged or Serrate protein) on one cell binds to the extracellular domain of the Notch protein on an adjacent cell

• This binding causes a shape change in the intracellular domain of the Notch protein

– This activates a protease - cleaves notch and allows & intracellular portion enters the nucleus

• In the nucleus the cleaved portion of Notch - activates a transcription factor of the CSL family - now it transcribes its target gene

Mechanism of Notch Action

Extracellular Matrix - Source of Developmental Signals

• Extracellular matrix - macromolecules secreted by cells into their immediate environment

– These molecules form a noncellular region in the spaces between cells

– A region critical for development

Extracellular Matrix - Source of Developmental Signals

• Cell adhesion, cell migration and the formation of epithelial sheets and tubes - depend on the ability of cells to form attachments to extracellular matrices

• The matrix may serve as a permissive substrate to which cells can adhere or in some cases it provides the directions for cell movement or the signal for a developmental event

Composition of Extracellular Matrix

• Collagen, glycoprotein molecules, proteoglycans (hundreds of polysaccharides covalently bonded to about 100 proteins - all of which are attached to an enormous polysaccharide) and many specialized glycoproteins such as fibronectin and laminin

– The glycoproteins - organize the matrix and cells into an ordered structure

Fibronectin

• Large glycoprotein dimer - serves as a general adhesive molecule - linking cells to one another and to other substrates such as collagen and proteoglycans

• Also functions in cell migrations - acting as pathways

• Fibronectin leads germ cells to the gonads & heart cells to the midline

Basal Lamina

• Type of extracellular matrix - upon which epithelial cell rest

• Composed of laminin and Type IV collagen

Extracellular Matrices in Developing Chick

Integrins

• Family of receptor proteins that bind fibronectin on the outside and the cytoskeleton on the inside - thereby uniting the two matrices

• Extracellular side - integrins bind a a sequence arginine-glycine-aspartate (RGD) - which is found in fibronectin and other adhesive molecules such as laminin

• Cytoplasmic side - bind to talin & a-actinin that bind to actin microfilaments

Integrin Binding

Basement Membrane-Directed Gene Expression

• Mouse mammary glands placed on tissue culture plastic - cell division genes on & genes for differentiated cell products (lactoferrin, casein, whey acidic protein) are off

• Present these glands with basement membrane that contains laminin - genes for cell division proteins are turned off

– Now the gene inhibiting cell division (p21) and gene for lactoferrin are turned on

Basement Membrane-Directed Gene Expression

• Eventually the mammary gland cells wrap the basement membrane about them, forming a secretory epithelium

• The genes for casein and whey protein are sequentially activated while p21(inhibits cell division) is still on and c-myc and cyclin D1 genes (cell division genes) are off

Basement Membrane-Directed Gene Expression

Gap Junctions

• Communication channels between adjacent cells

• Small molecules and ions can pass freely from one cell to the other

• In most embryos at least some of the early blastomeres are connected by by gap junctions

• Made of the protein connexin - each cell contributes 6 identical connexin molecules to form an intercellular channel containing a central pore

– The channel complex of one cell connects to the channel complex of the adjacent cell

Gap Junctions

Developmental Effects of Gap Junctions

• Blastomeres of eight cell stage injected with control antibody and antibody against connexin

Cross-talk Among Pathways

• Allows a cell to respond to multiple inputs simultaneously