Developmental Genetics Flashcards
Animal models
Genes and gene expression patterns are conserved, similar developmental pathways can be investigated- axis specification, pattern formation, organogenesis, concepts of induction and polarity
Conorhabditis elegans (nematode)
Short generation, complete cell fate map, alternate body plan, not a vertebrate
Drosophila melanogaster (fruit fly)
Short generation, easy to breed, lots of mutants, alternate body plan, must maintain live stock
Danio rerio (zebrafish)
Transparent embryos, easy to breed, small embryo difficult to manipulate
Xenopus laevis (clawed frog)
Large transparent embryo, can manipulate easily, tetraploid, makes genetics difficult
Gallus gallus (chicken)
Easy to observe and manipulate embryo, genetics difficult
Mus musculus (mouse)
Easy to breed, mammal, good genetics, embryo manipulation challenging
Genetic mediators
Paracrine signaling molecules- interactions between nearby cells
DNA transcription factors- control gene expression in cell, respond to external stimuli
Extracellular matrix proteins- scaffolding for tissues and organs, facilitate cell migration
Paracrine signaling molecules
Secreted into intercellular space, diffuse to nearby cells, four major families: fibroblast growth factor (FGF), Hedgehog proteins, wingless family (Wnt), transforming growth factor-beta (TGF-beta)
Signaling and receptors
Paracrine signaling molecules need receptors, cell-surface proteins that bind signal molecule cause gene expression changes- phosphorylation of proteins, signal transduction cascades
FGFR3 mutations
One of family of FGF receptors, common structure, 3 Ig-like domains, TM domain, split kinase domain, expressed in growing bones, skeletal dysplasias caused by mutation, most common due to autosomal dominant FGFR3 mutation
Achondroplasia
Skeletal displasia, disproportionately short stature (short limbs), macrocephaly, moderate increase in FGFR3 activity inhibits chondrocyte growth
Hypochondroplasia
Skeletal displasia, milder, less activation, fewer abnormalities
Thanatophoric dysplasia
Skeletal displasia, most severe, essentially lethal, very short limbs, highly activated receptor
Transcription factors
Bind DNA, activate or repress gene expression, usually multiple targets, cascade effect, causes pleiotropic effects
Families of transcription factors
Homeobox- HOX, PAX, EMX, MSX
High-mobility group (HMG)- SOX
T-box family- TBXs
SOX family
Prototype is Sry- sex determining region of Y, mammalian testis determining factor, regulates SOX9 expression in genital ridges
SOX9
Regulates chondrogenesis and Col2A1, mutation causes compomelic dysplasia, short limbs, sex-reversal of XY fetuses
Hirschsprung disease
Neural crest defect, enteric neurons do not develop properly, sporadic and familial cases though to be multifactorial, SOX10 one of several genes that causes phenotype
Extracellular matrix proteins
Secreted proteins that form scaffold for tissues, separate cells, provide matrix for migration, cells bind to ECM using specific proteins
Type 1 collagen- osteogenesis imperfecta
Collagen is highly modified triple-helix, glycosylated, hydroxylated, cross-linked, multiple helices form fibrils, mutations in glycines disrupt fibril formation, bone formation disrupted
Fibrillin-1 mutations
Coordinates microfibril assembly in ECM (with elastin), fibrillin-1 mutations in Marfan syndrome, elastin mutations in supravalvular aortic stenosis
Laminin mutations
Important in anchoring cells to ECM, LAMC2 mutations in junctional epidermolysis bullosa, epithelial does not attach, large blisters form on skin
Marfan syndrome
Tall and lanky, hypermobile joints, arachnodactyly, lens displacement, dilation of ascending aorta
Pattern formation
Pattern of tissues and organs established, general body plan laid down in embryo, regional separation
Stages of pattern formation
Define cells in the region, establish signaling centers, differentiation of cells in response to cues
Cell fate
Type of cell, function, longevity established during development, sonic hedgehog (SHH) involved in process
Sonic hedgehog (SHH)
Neural tube, somites, limbs, left-right axis
Holoprosencephaly
Severe form of SHH mutation, SHH attaches to cholesterol in membrane, midline brain defects caused by cholesterol biosynthesis inhibitors, severe mental retardation, early death, Smith-Lemli-Opitz syndrome
Axis specification
Vertebrate body plan has three axes- anterior/posterior, dorsal/ventral, left/right, anterior/posterior is first to form
HOX genes
Causes patterning along the axis, 4 clusters of similar genes, different chromosomes, expressed in specific spatial and temporal patterns
HOX gene expression
Up to 13 genes in each cluster, 3’ genes expressed earlier (temporal colinearity), 3’ genes expressed more anteriorly (spatial colinearity), regional specification
Homeotic transformation
HOX genes expressed from anterior boundary rearward in embryo, combination of expressed genes determines position, missing gene means segment identity wrong, segment transforms
Dorsal/ventral axis
Noggin and chordin are dorsalizing signals, Bmp4 is ventralizing signal, noggin and chordin bind Bmp4 and prevent binding to receptor
Left/right axis
Early event- asymmetric expression of SHH from notochord, causes left side expression of nodal (TGFbeta), rightward looping of heart tube results, mutation in dynein, motor protein for cilia
Zinc-finger protein of the cerebellum (ZIC3)
Gli transcription factor family, X chromosome, affected males- randomization defects, heterozygote females- L/R reversal, more common in conjoined twins than normal twins
Left/right axis defects
Random (situs ambiguus) or reversed (situs inversus)
Gli family regulation in Drosophila
Regulated by forming complex with protein similar to dynein
Limb development
FGF8 inductive signal, can induce entire limb, signal mediated by FGF10 expression, Wnt2b and Wnt8c maintain FGF10
FGF8 knockout
Loss of FGF8 in apical ectodermal ridge (AER) leads to shortened limbs
Limb growth signals
Proximal/distal growth stimulated by FGF2, FGF4, FGF8, zone of polarizing activity (ZPA) uses SHH to maintain AER, signals positional information along proximal/distal axis
Holt-Oram syndrome
Anterior defects, thumb/radius defects most common, T-box gene TBX5 mutated
Ulnar-mammary syndrome
Posterior defects, posterior digits/ulna most affected, TBX3 mutated, closely linked to TBX5, evolved from common gene
Organ formation
Complex, coordinate signals and gene expression, cellular interactions, cells become differentiated, must express proper genes for functions
Pancreas formation
Beta cells require IPF1 to express insulin, IPF1 mutations block pancreatic development, genes regulate insulin in addition to pancreatic cell maturation and differentiation
Transgenic mice
DNA microinjection, injection expression construct into pronucleus, insert in chromosome randomly, control expression by promoter, ectopic expression, overexpression, determine promoter function and structure
Knock-out mice
Using embryonic stem cells, homologous recombination to replace normal gene with altered counterpart, inject cells into blastocysts, breed to produce homozygotes, knock-out is complete disruption of function
