Neonatology and the Developmental- Evolutionary Parallel

1. Neonatology and the Developmental- Evolutionary Parallel • Endodermal and Ectodermal Tissues follow a common developmental sequence throughout all vertebrates • Disruption of this developemental sequence results in predictable consequences • In the surviving neonate, the consequences of developmental disruption equal congenital anomalies (e.g. holoprosencephaly, pulmonary hypoplasia) or morbidities of prematurity (e.g. RDS, apnea of prematurity). • We can flip this logic around by asking ourselves, “how can the developmental – evolutionary parallel be used to better understand these diseases?”

2. What is the Developmental- Evolutionary Parallel? Today 500,000,000 years ago Development: 10 weeks 20 weeks 30 weeks 40 weeks Perturbations result in spontaneous abortions Perturbations are associated with congenital anomalies Perturbations are associated with diseases of prematurity and birth The limits of viability The mesoderm is unfaithful in terms of the developmental – evolutionary parallel. By 21 days, the mesoderm of the human fetus has created the basic form of a salamander, but it takes another 21 weeks before the endoderm and ectoderm mature sufficiently for viability (at the saccular stage of lung development). But endoderm and ectoderm are faithful because of growth factor ontogeny (more later).

3. Notochordata (lampreys, lancets, hagfish) Today 500,000,000 years ago Larvea Pineal gland (the 3rd eye) Polymicrogyria Ram Jet Ventilation 2 = the notochord -/-PAX 6 (no pineal gland and…) Does he have 3 eyes too? GI tract = stoma + gut tube The lamprey gives us our hypothalamus, pituitary / pineal tracts and basal brain stem nuclei.

4. Elasmobranchs part 1 Today 500,000,000 years ago Development: 10 weeks 20 weeks 30 weeks 40 weeks proximal to distal gut development Elasmobranchs have 13 cranial nerves #13 = the nervous terminalis (an accessory olfactory nerve) “The brain follows the nose” holoprosencephaly BMP Elasmobranchs have keen smell and well developed olfactory cortex IGF-I + IGF-II FGF10

5. Elasmobranchs part 2 Today 500,000,000 years ago Development: 10 weeks 20 weeks 30 weeks 40 weeks If a fetus can’t breath in fluid (due to a swallowing defect, neuro or muscular defects, or insufficient amniotic fluid) the result is pulmonary hypoplasia Some Elasmobranchs develop the first gill chambers (operculums) and along with it they develop primary respiratory drive (a brain stem function). In parallel with evolution, fetal breathing starts in the first trimester. Elasmobranchs gave us our brainstem, cranial nerves and first highly developed lobe of cortex

6. Boney Fish Today 500,000,000 years ago Development: 10 weeks 20 weeks 30 weeks 40 weeks metanephric kidney IGFs & TGFa BMPs & FGFs Fish bring two crucial things to the developmental-evolutionary parallel: 1st – they evolve the first high resolution, complex eye into being (which comes with the optic cortex). 2nd – elasmobranchs convert ammonia to urea and permeate their tissues with it for buoyancy. Fish evolve the swim bladder for buoyancy as well as metanephric kidneys. They excrete all their ammonia. This become the basis for the terrestrial kidney. Pop Quiz: what is this syndrome?

7. Amphibians part 1 Today 500,000,000 years ago Development: 10 weeks 20 weeks 30 weeks 40 weeks TH The limit of gestational viability is the late cannicular phase of lung development. Artificial surfactant has little effect on the surface tension of lungs that have no air sacks but can almost completely normalize saccular lung. Amphibians stop here Mature type II pneumocytes are required to recycle surfactant and may explain why older infants (>30 weeks) require fewer repeat doses. BMP, EGF, FGF, TGFb, VEGF, SPARC Surfactant deficiency = respiratory distress syndrome

8. Amphibians part 2 Today 500,000,000 years ago Development: 10 weeks 20 weeks 30 weeks 40 weeks BMP + ? * Optic cortex and retinal density reach the optimum now that amphibians have to track flying prey (Bufo Marinus). Proximal – Distal effect Cloaca evolves as amphibians must hide their feces from predators & carry their eggs to water (precurser to colon and 1st durable gut modification since elasmobranchs). SIP occurs because the distal small intestine (ileum) is “under grown” in comparison to the proximal bowel, which distends it and perforates it with bowel gas *The skin becomes keratinized and semi- permeable to water as amphibians forage onto land. KGF ELBW infants have extreme insensible water loss. If poorly managed it leads to hypernatremia and is associated with IVH

9. Reptiles Today 500,000,000 years ago Development: 10 weeks 20 weeks 30 weeks 40 weeks “Reptilian lung” Reptiles have aveolar lungs and aveolar histology emerges after 34 weeks of development, coincident with final maturation of type II pneumocytes Keritinization is more complete after 28 weeks of gestation and water loss is less profound. Keritinization can be accelerated by stress. Apnea of Prematurity resolves around 30-32 weeks of gestation when the nuclei of the respiratory drive centers mature fully. Reptiles are the 1st vertebrates fully dependent upon active respiration SNO

10. Mammals part 1 Today 500,000,000 years ago Development: 10 weeks 20 weeks 30 weeks 40 weeks Transient Tachypnea is a disease of term infants that results from failure of clara cells and type II cells to insert ENaC in the cell surface (associated with c-sections / rapid progression) due to insufficient cortisol exposure. More Proximal – Distal effect Long gestations require large meconium resevoirs Development: 20 weeks 30 weeks 40 weeks Preterm NEC Term NEC Pre- ileocecal valve bacterial overgrowth formula feeds functional ileus Post ileocecal valve isechemic preconditions formula feeds rapid feeding advances s[cortisol] during pregnancy

11. Mammals part 2 Today 500,000,000 years ago Development: 10 weeks 20 weeks 30 weeks 40 weeks The phenomenon of postnatal brain development in higher mammals (primates) has created additional opportunity for developmental perturbation. There are two primary mechanisms of insult: 1) hypoxia-ischemia, which can occur either secondary to anoxic birth injury or in concert with prematurity and the combination of low O2 tensions + low flow states 2) Inflammatory cytokines associated with sepsis make premature infants even more vulnerable to PVL PVL is associated with cerebral palsy

12. Today 500,000,000 years ago The Take Home Message: prematurity infection teratogens gene defects Development: 10 weeks 20 weeks 30 weeks 40 weeks Perturbation Evolution Neonatal Well Being Fetal Development versus Neonatal Disease Neonatology So What?