BIOL 303 Lecture Notes - Lecture 4: Sirolimus, Myelin, Hair Cell
14 May 2018
School
Department
Course
Professor
Post-Embryonic Development
• Growth: as seen in previous lectures, more detailed mechanisms
• Metamorphosis: how do external changes occur
Growth
• Bases: Increase in cell number or cell size
• Cell proliferation: increase in # of cells, ex. Stem cells undergo rapid proliferation in the
brain, increasing the number of neurons
• Cell enlargement: increase in cell size, ex. Drosophila larval growth – involves increase
in cell size
• Increase in cell size example: neuronal development → you can think of it as an
extension of the somite, the axon becomes wrapped by the myelin sheath, adding to the
size of the nervous system (specifically white matter in the brain)
• Accretionary growth: cells secrete extracellular matrix proteins (secreted by fibroblasts,
for example) and fill the extracellular space Ex. cartilage, bone
Intracellular Pathways in the Control of Tissue
Growth
• Molecular pathways that regulate tissue or
organ growth: TOR and Hippo
• TOR Pathway: plays a major role in
promoting an increase in the size of the cell
• Hippo Pathway: plays a major role in
regulating cell proliferation
• The general action of both pathways is shown
in figure 1
TOR Pathway
• TOR = Target of Rapamycin
• Rapamycin = produced by some bacteria, has
anti-fungal activity → its major use is
immunosuppression (Ex. for transplant
procedures)
• TOR = a Ser/Thr Kinase → can phosphorylate
and hence regulate downstream processes
• Involved in the control of cell size
• Experiment: looking at TOR mutants in Drosophila → they are much smaller than
wildtype larvae → so TOR must have something to do with controlling cell size
• Experiment: using Drosophila adult wing as a model → the red line shows cells that are
TOR mutants within its bounds, with wildtype wing cells outside it → a property of
Drosophila wings is that every cell generates hair cells (which are cuticle structures) → in
the wildtype, the hair cells are much longer, therefore TOR is required for hair size on the
wings
Figure 1
find more resources at oneclass.com
find more resources at oneclass.com
Biol 303 March 29th
2
Pathway of TOR Action
• mTOR = mammalian TOR
• TOR is downstream of many factors like nutrient
receiving factors which can increase the activity
of TOR → TOR can lead to two things: 1)
rearrangement of actin skeleton (so cell looks
different) as well as 2) control of gene expression
→ together, these two downstream effects control
ultimate cell size
• See figure 2
Hippo Pathway
• Was first identified in Drosophila via a large-
scale genetic screen by Duojia Pan
• He looked for mutations that affected cell size →
cloned the corresponding genes
• Also looked at growth genes in mice → identified
the mammalian hippo pathway
• One major downstream target of Hippo is Yorkie (Yki) → Hippo inhibits Yki
• When you overexpress Yki, you see very dramatic increases in the size of the Drosophila
wing disc
Hippo Pathway in Drosophila
• Hippo is also a Ser/Thr Kinase → its target is Wts (another Ser/Thr Kinase)
• Wts phosphorylates Yki and inhibits it → preventing it from entering the nucleus
• Cell-cell contact somehow leads to the activation of Hippo pathway (and hence decrease
in cell proliferation and increase in cell death)
• In the inactivated Hippo pathway, Yki activates transcription of genes that promote
growth
Hippo Pathway in Mammals
• Occurs in the liver
• Some organs/tissues are insensitive to the Hippo pathway
Mechanisms limiting tissue growth and organ size
• Experiment: transplant limb bud from a larger salamander species to a smaller one → the
limb grows to full/ large size
• There must be intrinsic factors in the limb bud that determines its size
• Hypothesis: once a tissue reaches a certain size, and since tissues produce diffusible
factors, a certain level of factor diffusion must generate negative feedback to limit growth
→ dubbed “Chalones”
Myostatin
• Myostatin: a TGF-Beta family protein, an example of a Chalone in vertebrate muscle
Figure 2
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Post-embryonic development: growth: as seen in previous lectures, more detailed mechanisms, metamorphosis: how do external changes occur. Growth: bases: increase in cell number or cell size, cell proliferation: increase in # of cells, ex. Stem cells undergo rapid proliferation in the brain, increasing the number of neurons: cell enlargement: increase in cell size, ex. Drosophila larval growth involves increase in cell size. Figure 1 for example) and fill the extracellular space ex. cartilage, bone. Tor mutants within its bounds, with wildtype wing cells outside it a property of. Drosophila wings is that every cell generates hair cells (which are cuticle structures) in the wildtype, the hair cells are much longer, therefore tor is required for hair size on the wings. Together, these two downstream effects control ultimate cell size: see figure 2. In the inactivated hippo pathway, yki activates transcription of genes that promote growth.
