Chapter 4: Molecular Basis for Embryonic Development Flashcards
transcription factors
proteins possessing domains that bind to the DNA of promoter or enhancer regions of specific genes
also possess domain that interacts with RNA polymerase II or other transcription factors and consequently regulates the amount of mRNA produced by that gene
some are general that can be found in virtually all cells while others are extremely specific for certain types of cells and stages of development
signaling molecules
leave the cells that produce them and exert their effects on others, which can be neighboring cells or cells located at greater distances
many are members of the growth factor family
signaling molecules bind as ligands to receptor molecules that are often transmembrane proteins protruding through the plasma membrane of cells that they affect
signal transduction pathway
set off by the formation of a signaling molecule-receptor molecule complex; result in cascade of events that transmits the molecular signal to the nucleus of the responding cell
homeodomain proteins
contain a highly conserved homeodomain region of 60 amino acids
homeodomain: type of helix-loop-helix region
homeobox
the 180 nucleotides in the gene that encode the homeodomain
maternal effect genes
in Drosophila, establish the dorsoventral and anteroposterior axes of the embryo
gap genes
control the first step of segmentation in Drosophila; subdivide the embryo into broad regional domains
pair-rule genes
control the second step of segmentation in Drosophila; involved in the formation of seven pairs of stripes along the craniocaudal axis of the embryo
segment-polarity genes
control the third step of segmentation in Drosophila; work at the level of individual segments and are involved in their anteroposterior segmentation
homeotic genes in Drosophila
impart specific or regional characteristics to the newly formed segments;
found in the antennapedia complex and the bithorax complex
antennapedia-bithorax complex in Drosophila
consists of 8 homeobox-containing genes located in 2 clusters on the chromosome
mice and humans have at least 39 homologous homeobox genes
vertebrate Hox genes
paly a prominent role in craniocaudal segmentation of the body and their spatiotemporal expression proceeds according to very regular rules
genes are activated and expressed according to a strict sequence in the 3’ to 5’ direction
originally described to operate along the main body axis;; later discovered to be involved in developing organs or regions such as the gut, limbs, and internal and external genitalia
loss-of-function mutations
result in posterior-to-anterior transformations (cells of a given segment form the structural equivalent of the next most anterior segment)
gain-of-function mutations
result in anterior-to-posterior structural transformations (cells of a given segment form the structural equivalent of the previous most posterior segment)
Pax gene family
consists of 9 known members;
homologous to Drosophila pair-rule segmentation genes
all contain a paired domain of 128 amino acids that bind to DNA;; some also contain entire or partial homeobox domains and conserved octapeptide sequence
play important role in sense organs and developing nervous system; also involved in cellular differentiative processes when epithelial-mesenchymal transition occurs
POU gene family
Pit1: gene uniquely expressed in the pituitary
Oct1 and Oct2; Oct4 plays important role in early cleavage
Unc86: expressed in nematode
contain a homeobox, region encoding 75 amino acids, which also bind to DNA through a helix-loop-helix structure
Lim proteins
large family of homeodomain proteins; some bind to DNA in the nucleus and others are localized in the cytoplasm
involved in some stage of formation of virtually all parts of the body
no Lim=headless mammal
Dlx gene family
group of genes that have been phylogenetically conserved; six members
play important role in patterning, especially outgrowing structures, in early embryo
operate in pairs which are closely associated with Hox genes
involved in morphogenesis of jaws and inner ear and in early development of the placenta
Msx genes
small, highly conserved family of homeobox-containing genes; only two in humans;
play important roles in embryonic development; especially in epitheliomesenchymal interactions in the limbs and face
generally inhibitors of cell differentiation in prenatal development
in postnatal life; maintain proliferative capacity of tissues
T-box (tbx) gene
takes name from brachyury (T) locus; recognized originally to cause short tails in heterozygotic mice
involved in development, with roles such as inducing the mesodermal germ layer, and coordinating outgrowth or either the arm or the leg
basic helix-loop-helix proteins
contain a short stretch of amino acids in which two alpha-helices are separated by an amino acid loop
helices region (with adjacent basic regions) allows the regulator protein to bind to specific DNA sequences
forkhead (Fox) genes
family of transcription factors
contain a winged helix structure; expressed in many developing organs throughout the body; tend to have microscopically distinct domains within the developing organ and can work together to direct the morphogenesis of a structure
zinc finger transcription factors
proteins with regularly placed cystidine and histidine units that are bound by zinc ions and cause he polypeptide chain to pucker into fingerlike structures which can then be inserted into specific regions of the DNA helix
Sox genes
large family that have in common HMG domain
SRY gene is one example;
work in concert with other transcription factors to influence the expression of their target genes
HMG (high mobility group) domain
found on Sox genes; unusually for a transcription factor in that, with a partner protein, it binds to 7 nucleotide on the minor instead of the major groove on the DNA helix and causes a pronounced conformational change in the DNA
WT1 gene
isolated gene that in prenatal life plays a prominent role in formation of both the kidneys and the gonads
crucial for the development of early forms of kidney and for formation of definitive adult kidney; necessary for formation of the gonads
transforming growth factor-beta family
numerous molecules that play a wide variety role during embryogenesis and postnatal life
regulated by several molecules that bind to them in the extracellular space
TGF-beta 1-5
mesodermal induction
myoblast proliferation
invasion of cardiac jelly by atrioventricular endothelial cells
activin
granulosa cell proliferation
mesodermal induction
inhibin
inhibition of gonadotropin secretion by hypophysis
Mullerian inhibiting substance
regression of paramesonephric ducts
decapentaplegic
signaling of limb development
Vg1
mesodermal and primitive streak induction
BMP-1 to BMP-15
induction of neural plate, induction of skeletal differentiation, and other inductions
exert their effects by inhibiting other processes in the embryo
nodal
formation of mesoderm and primitive streak, left-right axial fixation
glial cell line-derived neurotrophic factor
induction of outgrowth of ureteric bud, neural colonization of gut
lefty
determination of body asymmetry
fibroblast growth factor family
play important roles in a variety of phases of embryonic development and in fulfilling functions, such as stimulation of capillary growth, post natal body
mainly regulated farther downstream; secreted FGFs are closely associated with extracellular matrix and must bind to heparan sulfate to activate their receptors
means of regulating FGF
modification of their interaction with heparan proteoglycans in the receptor complex
regulation at the membrane of the responding cell through the actions of transmembrane proteins
intracellular regulation by molecules, such as SPROUTY, which complex with parts of the signal transduction machinery of the responding cell
hedgehog family and sonic hedgehog
protein with highly conserved N-terminal region and a more divergent C-terminal region
after its synthesis and release from RER, the signaling peptide is cleaved off and glycosylation occurs on the remaining peptide;
still within the cell, shh peptide undergoes autocleavage through the catalytic activity of its C-terminal portion, while the N-terminal segment becomes covalently bonded with cholesterol
the N-terminal peptide is secreted from the cell, but it remains bound to the surface off the cell that produced it;; all the signaling activity of shh resides in the N-terminal segment
through the activity of another gene product, the N-terminal segment of shh, still bound to cholesterol is released from the cell;
C-terminus plays no role in signaling
shh signaling pathway on target cell
shh, still with cholesterol, binds to Patched (Ptc) receptor, closely associated with transmembrane smoothened (smo)
Ptc normally inhibits smo, but shh inhibits Ptc, thus allowing smo to give off intracellular signal
Wnt family
plays dramatically different roles in different classes of vertebrates; in mammals, plays important role during gastrulation (stimulate cellular proliferation that is required to bring organs to their normal proportions)
often interact with components of the ECM;
Wnt-inhibitory factor-1 (WIF-1) and Cerberus directly bind to the Wnt molecule, inhibiting it
dickkopf effect inhibition by binding to receptor complex
chordin, noggin, gremlin
inhibit activity of BMP, which itself is an inhibitor
inhibiting the inhibitor a common trend in developmental biology signaling molecules
positive and negative regulators of growth
positive: shh and FGF
negative: some BMP
cell surface receptors
typically transmembrane proteins with extracellular, transmembrane and cytoplasmic domains
extracellular domain has a binding site for the ligand; binding of ligand affects conformational change in the cytoplasmic domain
two main types: (1) intrinsic protein kinase activity and (2) receptors that use a secondary messenger system to activate cytoplasmic protein kinases
lateral inhibition
when one cell from a group of developmentally equivalent cell differentiates into a dominant mature cell type and signals its subservient neighbors to prevent them from differentiating into the same cell type
Notched signaling pathway
common mechanism of lateral inhibition
cell surface receptor with a large extracellular domain and a smaller intracellular domain
becomes activated when combines with ligands Delta or Jagged that extend from the surface of the dominant cell, setting off pathway that inhibits the neighboring cell from differentiating into the dominant phenotype
complexing of Notch with ligand stimulates an intracellular protease reaction that cleaves off the intracellular domain of the Notch molecule
intracellular domain translocated to nucleus; on the way becomes associated with regulatory proteins such as deltex;
in the nucleus, intracellular domain of Notch combines with several helix-loop-helix transcription factors and complex binds to DNA of gene called enhancer of split
product of enhancer of split is a transcription factor that regulates other genes
signal transduction
process by which signal provided by the first messenger is translated into an intracellular response
binding of signaling molecule to receptor resulting in a conformational change of the receptor
sets of chain reaction that carries the signal to the nucleus, where it ultimately influences gene expression
receptor tyrosine kinase (TRK) pathway
members of FGF family do this
FGF binds to receptor, G protein near receptor becomes activated and results in RAS ==> RAF ==> MAP kinase ==> ERK which enters nucleus and phosphorylates transcription factors
TGF-beta and Smad proteins
TGF-beta binds to type II serine-threonine kinase receptor which complexes with type I receptor
two different Smad proteins, R-Smad and Co-Smad dimerize and enter the nucleus; binds with cofactor and is then capable of binding with some regulatory element on DNA
Wnt pathway
binding of Wnt to transmembrane receptor, Frizzled,
Frizzled interacts with Disheveled, which ties up a complex of numerous molecules (destruction complex) which in the absence of Wnt causes the degradation of beta-catenin
if beta-catenin is not destroyed, it enters the nucleus where it acts as a powerful adjunct to transcription factors that determine patterns of gene expression
Hippo pathway
regulates the growth of organs throughout the animal kingdom
small RNAs
small noncoding RNA molecules that exert an enormous array of influence on gene expression, mainly at posttranscriptional levels
can be divided into two groups: those that act during gametogenesis and those that act during embryogenesis
gametogenesis: Piwi-interacting RNAs (piRNAs) important in spermatogenesis and endogenous small interfering RNAs (endo-siRNAs) play vital roles in oogenesis
miRNAs expressed in somatic tissues during embryonic development
vitamin A (retinol) and its metabolite, retinoic acid
retinol binds to retinol-binding protein, which attaches to specific cell surface receptors
retinol then released and binds to cellular retinol binding protein (CRBP I); all-trans retinol then converted into all-trans retinoid
CRBP I and CRABPI (cellular retinoic acid-binding protein) regulate the amount of retinoids that enter the nucleus
retinoic acid enters the nucleus when released from CRABP and binds with dimer heterodimer retinoic acid receptor (RAR), retinoid X receptor (RXR)
this complex then binds to retinoic acid response element (RARE) on DNA in the enhancer region of a gene
