SDB 2011: A sick afternoon

Incoming! Here’s another dump of my notes from yesterday afternoon. I’ll be hitting you with more later today.

Disease is the pretext here, but it’s really all about development.

15:30-17:00 Session 4: Development and Disease (Chair: Jack Somponpun [Univ. Hawaii]; co-Chair: Jacqueline Ho [UPMC])

15:30-16:00 Jacqueline Ho (Children’s Hospital of Pittsburgh UPMC) “microRNAs in kidney development and disease”

Congenital anomalies are most common cause of renal failure in children.  Kidneys form from metanephric mesenchyme by induction from branching tubule – lots of interactions and opportunities to go awry. She’s looking at effects of miRNA. Loss of mRNAs in podocytes of glomerulus using transgenic mice leads to fetal death — they are necessary for formation of filtration barrier. Loss of miRNAs in nephron progenitors leads to depletion of population. Imbalance between selection for differentiation vs. Self-renewal?

There is no difference in proliferation. There is an increase in apoptosis.

Next problem is sorting out which of the many miRNAs deleted are important. Using bioinformatics tools to predict miRNA target interactions. Found candidate gene target, Bim, and identified miRNAs that might be modulating it’s expression.

Balance between survival (Bcl2) and apoptosis (Bim) that is tipped by miRNAs.

  16:00-16:20 Jack Somponpun (Faculty, Univ. Hawaii) “Reduced embryonic Six2 expression compromises nephron development and leads to osmoregulatory defect associated with post-natal fluid and electrolyte handling”

Variation in nephron number in population: as few as 200000′ as many as 2.5 million, average of about a million. Is this normal diversity or is it a consequence or cause of health problems? Kidneys are most important organ for regulation if bulood pressure. What is the significance of low nephron number?

Brachyrrhine mutant mice — greatly reduced kidney size, shows haploinsufficiency. Six2 is expressed strongly in embryonic kidney; thought to play a role in maintaining size of progenitors populations and preventing premature differentiation. Looked at Br mouse and also used siRNA to reduce six2 in cell culture system.

Br mutants have reduced number of nephron rudiments and reduced Six2 expression.

Inhibition of Six2 in culture also leads to reduced number of nephron rudiments. Also up regulates WT1, reduces Pax2, Cited1.

Reduced kidneys in Br mice have physiological effects. Can’t cope as all with increased salt in diets — hypeerosmolalitu, hypernatremia, polydipsia, with urine-concentrating defect, comparable to chronic renal failure.

  16:20-16:40 Grant Miura (Postdoc, UC San Diego) “The T-Box Transcription Factor Tbx20 is required for the maintenance of proper cardiac chamber size”

Early development of heart: mustw balance size of ventricle vs. Atrium. Laf mutant reduces atrium size. Tinkeering with BMP pathway affects relative size of atrium/ventricle. BMP Important; what are other signals, and what are downstream targets? Screened small molecules known to cause cardiovascular defects. 

Searched for genes with SMAD binding sites, which led to Tbx20 gene. Tanscription factor with conserved expression in flies and vertebrates. Tbx20 morpholinos caused serious cardiac edema, otherwise normal. Decreased both atrial and ventricular size, but early specification was normal. Doesn’t look like laf at all. Regulates proliferation or maintenance?

  16:40-17:00 Denise Al Alam (Postdoc, Saban Research Institute) “FGFR2b signaling is required for the formation of lipofibroblasts in the developing mouse lung”

Bronchopulmonary dysplasia — preemies treated with oxygen end up with surfactant deficiency, decrease of lipofibroplasts and FGF10. lipofibroblasts required for surfactant synthesis. FGF10 through FGFR2b required for differentiation. Used Dom-neg receptor to knock down FGFR2b.  Reduces lung differentiation.