L50: Genetics of Development

Question 1

Compare the impact of problems during the first 4 weeks, weeks 5 to 8 and in later stages of development

Answer 1

1.) 1-4 weeks (blastogenesis): abnormalities during this period produces multiple major abnormaities in entire embryonic regions. Example = VACTERL 2.) 5-8 weeks (organogenesis): abnormalities during this period affects specific organs and produces single major anomalies. Example = congenital heart defects 3.) 9+ weeks: major organs have formed, abnormalities here will have mild effects on the individual. Example = single palmar crease

Question 2

Give figures for the genetic and environmental contributions of the burden of congenital malformations

Answer 2

• In over 50% of birth defects, no cause can be identified, remaining are: - Genetics: 50% have complex inheritance, 25% caused by chromosomal defects, 20% caused by single-gene mutations - Non-genetic factors such as maternal medication and infections = 5%

Question 3

What is VACTERL association? What is an association?

Answer 3

• vertebral defects, anal atresia, cardiac abnormalities, tracheo-esophageal fistula, renal and limb abnormalities - defects are through to occur in blastogenesis phase of development - risk factor: maternal diabetes - association = group of birth defects that for unknown reasons often occur together

Question 4

Contrast regulative and mosaic development

Answer 4

• Regulative phase: cells are functionally equivalent and loss of part of embryo can be compensated for by neighbouring, similar cells - Mosaic phase: Loss of a cell in this phase cannot be compensated for and will lead to loss of tissue that dead cell was fated to become

Question 4

What do defects in Shh cause?

Answer 4

• Left/right asymmetrical defects – situs inversus

Question 4

Two sets of terms used to describe a birth defect?

Answer 4

1.) Malformation, deformation, disruption 2.) Sequence and syndrome

Question 6

Describe the function of the node

Answer 6

• Node is the anterior end of the primitive streak. Node secretes proteins known as noggin and chordin and induce dorsal development in a concentration-dependent manner

Question 6

What is Treacher-Collins Syndrome?

Answer 6

• Pts present with cleft palate, micrognathia (small jaw), down slanting palpebral fissures and malar hypoplasia (underdeveloped zygoma). - This is an AD disorder. Individuals have high risk for complications relating to this disorder – eg. Cardiovascular.

Question 7

Identify the first visible axis in the developing embryo

Answer 7

• Anterior/posterior axis. This is defined by the primitive streak, which is defined by the position of the entry of the sperm into the egg. Node is the anterior end of the streak and the groove is the primitive streak and serves as the anterior/posterior axis.

Question 8

Name the five most frequent birth defects. Give frequencies

Answer 8

1.) Heart defects – 1/100-200 2.) Pyloric stenosis – 1/300 3.) Neural tube defects – 1/1000 4.) Orofacial clefts – 1/700-1000 5.) Clubfoot – 1/1000

Question 9

Describe pre-implantation diagnosis

Answer 9

• In morula phase, cell can be removed from embryo and examined for chromosomal aberrations during pre-implantation diagnose. As this is the regulative phase of development, the remaining cells continue to develop into a perfectly normal embryo.

Question 10

Explain which germ layer gives rise to which organs

Answer 10

• Epiblast gives rise to all three germ layers in a process known as gastrulation: ectoderm, mesoderm and endoderm - Ectoderm forms skin and nervous system - Mesoderm forms bone, muscle and most internal organs - Endoderm forms cells of gut and lung epithelium

Question 11

Explain patterning. Discuss role of signaling molecules that are necessary for this to occur

Answer 11

• Following specification of axes, patterning takes place. Patterning defines which end of undevelopmed mass of cells is head, which is tail. It segments cells to define which parts become head, thorax, abdomen etc. - Patterning along ant/post axis is determined by homeobox (HOX) genes, which are a family of transcription factors containing a special DNA binding domain called homeodomain. There are 4 HOX clusters on 4 chromosomes - Expression of each of the genes belonging to a cluster correlates with position of respective cell in embryo and with timing of expression. Each cell along axis experiences a different ratio of expression of different HOX genes. Ultimately, the pattern of HOX gene expression determines fate of a cell in segment.

Question 12

Explain the robustness of development and role of chance in expression of developmental defects

Answer 12

• Development must be tightly regulated: one extra round of cell division early in development is likely fatal, extra cell division late in development can lead to segmental overgrowth - Robustness: disturbances to normal developmental process occur regularly, these disturbances are countered by regulatory mechanisms

Question 13

List three axes in embryological development

Answer 13

• Anterior-posterior axis - Dorsal-ventral axis - Left-right axis

Question 14

List three axes and discuss the function of each, what gene/factor is responsible for formation of this axis?

Answer 14

1.) Anterior-posterior axis - First visible structure defined by primitive streak with groove. Node is at the anterior end. Nodal gene is responsible for formation of this axis 2.) Dorsal-ventral axis - Secreted proteins noggin and chordin are secreted from cells in the node and induce dorsal development in a concentration-dependent manner 3.) Left-right axis - Asymmetric expression of the gene for the signaling protein Shh: sonic hedgehog from the notochord causes left/right asymmetry. This leads to asymmetric expression of nodal on the left-side that initiates development of the heart tube.

Question 15

Identify axes in the embryo and limbs

Answer 15

• Shoulder-to-fingertip is designated proximal-distal development - Thumb-to-fifth finger is designated anterior-posterior development - Dorsum-to-palm is dorsal-ventral development

Question 16

Contrast malformation, deformation and disruption. Examples

Answer 16

• Malformation: intrinsic abnormality in developmental process. Eg. Polydactyly - Deformation: extrinsic influence on development of the affected tissue. Eg. Oligohydramnios - Disruption: destruction of developing tissue. Eg. Amniotic bands

Question 17

Contrast isolated anomalies, sequences and syndromes

Answer 17

• Isolated anomalies: single problem that can be sporadic or multifactorial in order that just affects a single body region. Ex: cleft palate. Major anomalies = anomalies requiring surgical or cosmetic consequences. Minor anomalies = little impact on well-being of pt – can give diagnostic clues about presence of a syndrome. - Sequences: cascade of events, starting from isolated anomaly and leading to multiple malformations - Syndromes: affect several body regions and often display chromosomal or Mendelian inheritance.

Question 19

Name 5 processes by which cells participate in development

Answer 19

1.) Gene regulation by TFs and chromatin modification 2.) Cell-cell signaling (direct contact or morphogens) 3.) Development of specific cell shape and polarity 4.) Movement and migration of cells 5.) Programmed cell death

Question 20

Stages of development

Answer 20

1.) early development (regulative, mosaic and gastrulation phases) 2.) axis formation 3.) patterning along axes

Question 22

Give epidemiology figures for congenital malformations

Answer 22

• 2-3% of children are born with a recognizable birth defect - 20% of total mortality, birth defects are most common cause of infant death in US - Another 20% of infant deaths are caused by prematurity, which also can be considered a failure of normal development

Question 23

What is situs inversus and situs ambiguous, what causes it?

Answer 23

• Both are defects in left/right axis formation - Situs inversus: all organs are complete mirror images in what is normally found (known a situs solitus). Usually asymptomatic - Situs ambiguous describes a more serious condition in which orientation of organs is randomized. This is usually accompanied by heart defects.

Question 24

What is the Pierre Robin Sequence?

Answer 24

• Collagen disorder, generalized growth retardation, neurogenic hypotonia, oligohydramnios leads to …. - Mandibular hypoplasia leads to …. - U-shaped cleft palate and micrognathia (small jaw/chin)