GROWTH. Fetal Development Cells grow, differentiate specific organs Genes turned on, off...

GROWTH

Fetal Development

• Cells grow, differentiate specific organs

• Genes turned on, off– Regulate cell structure, function

• Cell life cycle– G0 – not committed to cell division– G1 – preparatory to cell division– S – DNA replicated– G2 – some protein synthesis– M – cell division

Growth

• Hypertrophy

• Hyperplasia

• Incr’d cell molecules

• Hormones– Materials avail to cells– Stim cell division– Stim secr’n– Commonly promote growth

• Absence atrophy

Growth Hormone

• Secr’n from somatotrophs– GHRH stims

• Episodic• If continuous downreg’n GHRH receptors,

blunted response

– SST inhibits

Somatotroph Receptors

• GHRH ad cyclase cAMP PKA, and PLC IP3, DAG, Ca+2– Expr’n induced by normal cortisol levels

• SST inhib’n ad cyclase– Receptor G-prot coupled, heptahelical– Gen’l turn-off response (secr’n, cell prolif’n,

etc)

Growth Hormone

• Expression GH gene enhanced– PROP-1 (related to function of Pit-1)– cAMP in somatotrophs

• Coactivators of expression– Normal cortisol levels– Normal thyroid hormone levels

• 40-50% complexed to GH-BP– Cleaved extracell domain of GH receptor– Not avail to receptors (hormonal reservoir)

GH Receptor

• Hematopoietic receptor superfamily

• 3 domains– Extracell binding– Single transmembrane segment– Intracell

• Single GH binds 2 receptors (dimerization)– Activates Jak-STAT pathway

• Highly species specific

GH Function Discovered @ Bones

• Indirect stim’n growth of epiphyseal region– Stim’n prolif’n

• Cartilage cells (epiphyseal growth plate)• Fibroblasts• Periosteum cells

– After epiphyseal closure, periosteum/ perichondrial growth only

– Increased bone mass, bone mineral density

• Through “sulfation factor”

Somatomedins = Insulin-Like Growth Factors

• In plasma

• Controlled by GH

• Promotes inc’n sulfur – Cartilage– Skeletal, other connective tissues– Organs

Dual Effector Theory

• GH directly stim’s differentiated state of some cells New cells more sensitive to IGFs– Book: GH injected into bone growth plate

bone growth• Incr’d # local IGF-I immunoreactive cells w/in

chondrocytes• Diff cell targets for GH, IGF

– GH stim’s cell division of stem-cell like cells clonal expansion

– Then IGF-I enhances initiated clonal expansion

IGF-I, II• Structure

– 3D sim to insulin• Gene duplication 2nd chromosome? Funct’l division?• Some affinity for ins receptor

– Single chain• I – 70 aa’s• II – 67 aa’s

• Secr’n I dependent on GH

• II more abundant in human adult plasma

IGF Binding Protein

• 150 kDA• Complexes most IGF’s in plasma• GH-dependent• Prod’d by liver

– 6 diff prot’s expressed in diff tissues– IGF-BP3 binds most IGF

• Acid-Labile Subunit– Glycoprot– Interacts w/ IGF-BP-3

Table IIFunctional characteristics of human IGFBP

IGFBP Potential functions Cell surface/matrix binding

Modification by proteolysis

1 Minor serum carrierPotentiates/inhibits IGF action

Yes Yes

2 Minor serum carrierPotentiates/inhibits IGF action

No Yes

3 Minor serum carrierPotentiates/inhibits IGF actionIndependent modulator of cell proliferation

Yes Yes

4 Inhibits IGF action No Yes

5 Potentiates/inhibits IGF action Yes Yes

6 Potentiates/inhibits IGF action? No Possible

7 Inhibits IGF action Unknown Unknown

• May interact w/ target cells– Some bind to cell surfaces– Facilitate hormone/receptor interaction?– More dynamic than “hormone sink”

Plasma IGF-I

• Incr’s from birth

• Peaks in pre/early adolescent– Impt to prepubertal growth spurt– Accompanied by incr’d urinary GH

• Slowly decreases

• Negatively feedback inhibits GH secr’n– Normally hypersecr’n prevented by rise in

circ’ng IGF-I

• Set-point of neg feedback elevated during puberty– Estradiol may re-set by stim’ng hypothal E2

receptors GHRH effect– BUT no change in sex steroid prod’n

correlates w/ IGF-I, GH decline

Thyroid Hormones Impt to Growth

• Nec to maintain GH prod’n– Permissive: GH causing IGF-I stimulation– Permissive: IGF-I growth promotion

• Paracrine/autocrine functions also– IGF gen’d @ physio levels at diff tissues

IGF Receptors• IGF-I

– Ligand-dependent tyr kinase activity– Autophosphorylation– Sim structure, function as insulin receptor

• Heterotetramer• May form hybrid tetramers w/ ins receptor

– IGF-I > IGF-II >> insulin• Ins receptor binding insulin > IGF-II > IGF-I

• IGF-II– Does not bind insulin– Impt to clearing IGF-II from ECF

Functional consequences of IGF-I receptor b subunit activation.Binding sites for intracellular signaling molecules are indicated. Assignment of functions to specific phosphotyrosines is described in the text. Dotted areas in the extracellular a subunit indicate the cysteine-rich domains; dashed areas in the intracellular b subunit indicate the tyrosine kinase domains. IRS-1, insulin receptor substrate-1; GAP, GTPase-activating protein.

Downstream targets of IGF-1R. Schematic diagram showing the proposed signaling pathways for the IGF-1R (see details in the text). The crosstalk with other growth factor tyrosine kinase receptors is not shown. The 85 kDa and 110 kDa subunits of the phosphatidylinositol-3 kinase are shown as p85 and p110.

Table IIISummary of SH2-containing proteins that bind to

IRS-1 or IGF-1

Protein Function Specificity

Grb-2/Grb-10   Adapter, binds mSos; Grb-2-mSos complex activates p21ras

IRS-1, IGF-1R

GAP Ras GTPase-activating protein IGF-1R

SH-PTP2(Syp) Protein tyrosine phosphatase IRS-1, IGF-1R

p85 Regulatory subunit of the PI 3-kinase IRS-1, IGF-1R

Nck Adapter protein; unknown function IRS-1

Shc Adapter protein, can bind to the Grb-2-mSos complex

IRS-1, IGF-1R

Other GH Activities

• Diabetogenic (opposes insulin, IGF)– Stim’s lipolysis decr’d glu metab and

substrates for glu form’n Incr’d plasma FFA hepatic glu output Incr’d muscle mass (abused)– Requires glucocorticoid permissive action – Depletes triglyceride stores of adipocytes– Protects against hypoglycemia in adults

• Inhibits differentiation of preadipocytes to adipocytes

• Stim’s prod’n fibrinogen in liver– Contributes to atherosclerosis,

thromboembolism– W/ hyperglycemia, hyperlipidemia

• Affects connective tissue of skin– Physio regulation hair follicles, sweat glands

• Brain effects– Transported– Reaches brain via CSF– Apparent growth factor-like

Insulin Role in Growth

• Book: children of diabetic mothers (hyperinsulinemic) have incr’d stature

• Req’d for full anabolic effect of GH– Glu uptake incr’d w/ insulin energy for prot

synth– Aa uptake incr’d w/ insulin incr’d prot synth– Act’n translation capacity w/ insulin– Can bind IGF receptors @ high concent

Prolactin Role in Growth

• Sim structure as GH

• Gene expr’n of both regulated by Pit-I– Pituitary-specific transcription factor– Also impt to TSH subunit expr’n– Mutation deficiency almost all ant pit

hormones

• Receptors sim– Probably not tyr kinase related

• Impt to growth/dev’t mammary glands– With estrogens, glucocorticoids

• Directly affects growth, function of gonads– Modulation effects of LH/FSH ??

• Effects immune system– Lymphocyte growth factor– Accelerates T-cell-dependent responses

• Impt in amphibian growth– Tail, gill growth– Limb regeneration

Nerve Growth Factors

• Impt to central, peripheral NS cell differentiation, growth

• Reciprocal actions of periph neurons/ target tissues– Periph tissues biochem’s enhancing

growth/diff’n of nearby neurons• May stim innervation of tissues

– Neurons biochem’s impt to dev’t target tissues

NGF

• Released by mouse tumor hypertrophy chick ganglia

• Prod’d in salivary gland– High concent– Regulated by sex steroids– Impt to fighting

• Peripherally prod’d crucial to ANS periph symp postganglionic neurons– Fetal: animal symp ns completely dependent– Adult: maintenance of symp ns

• Repair, regeneration, protection of neurons

Mouse Salivary NGF

• Used for study

• 3 polypeptide chain types (, , )

• Dimers held by covalent bonds

• Synth’d as proNGF is endopeptidase impt to structural maintenance in secretory

granule (?) -- nerve growth promoting activity

• Homologous to insulin– Similar activities– Binding to cell membr enhanced

anabolism (cell growth)– May have evolved from proinsulin gene

• NGF Receptors– Two types, perhaps diff functions

• High affinity binding may require both types

• Binding TrkA receptor act’n receptor tyr kinase sev signaling cascades– PLC/DAG/IP3/PKC– Ras-mediated act’n of map kinase

• Shc/Grb-2/Sos-1• Raf/Mek/Erk• Fos+jun AP-1 (transcr’n factor)

– Other factors: Egr, CREB• Impt to neurite form’n, survival symp neurons

NGF Effects

• Synth specific enz’s nec to catecholamine synth– Tyr hydroxylase– DA -hydroxylase

• Stim nerve fiber outgrowth– Neurofilaments in axons

• Through posttranslational process

– Ornathine decarboxylase impt?• Key in polyamine biosynth• Impt to cell division/growth regulation

• Directs growing symp nerve fibers toward target tissues– In fetal dev’t, correlation between [NGF],

mRNA for nerve fiber prot’s, density nerve fiber prot’s

– Synth’d by many cells• Epithelia• Smooth muscle cells• Fibroblasts• Schwann cells

– Not mitogenic– Contued exposure essential to survival in

some cell pop’ns

Figure 4. The nerve growth cone is located in the distal chip of a growing axon and its movement plays an important role in axon elongation and guidance (left). When the nerve growth cone receives repulsive stimuli, it becomes collapsed (right) and the axon stops growing to the direction.

• Neurotropic in mammalian CNS– Brain NGF

• Molecules• mRNA• Receptors• -Sensitive neurons

– Regulates differentiation cholinergic neurons in basal forebrain

– Counteracts learning, memory deficits in lesioned animals

– Alzheimer’s therapy??