The Peter Pan paradigm

Abstract

Genetic and environmental agents that disrupt organogenesis are numerous and well described. Less well established, however, is the role of delay in the developmental processes that yield functionally immature tissues at birth. Evidence is mounting that organs do not continue to develop postnatally in the context of these organogenesis insults, condemning the patient to utilize under-developed tissues for adult processes. These poorly differentiated organs may appear histologically normal at birth but with age may deteriorate revealing progressive or adult-onset pathology. The genetic and molecular underpinning of the proposed paradigm reveals the need for a comprehensive systems biology approach to evaluate the role of maternal-fetal environment on organogenesis."You may delay, but time will not" Benjamin Franklin, USA Founding Father.

Figure 1

Lung development and the effects of developmental disruption. A-Normal lung differentiation; B-Disrupted growth; C-Premature transition resulting in abbreviated pseudoglandular stage; D-Delayed transition leading to incomplete canalicular and saccular/alveolar stages.

Figure 2

Stem cell differentiation during organogenesis. Progression through varying transit amplifying (TA) cell stages of functional maturity (bottom gray scale) called temporal states (TS) A-C. Various geometric shapes (stars, ovals, triangles, etc) represent either intracellular, extracellular, or membrane associate markers of differentiation.

Figure 3

Architecture and developmental programming. Normal architecture depends on building layers that are based on both quantity and timing of components with an overall structural size limitation (Panel A). Premature activation of subsequent stages disrupts primary base structure requiring downstream components to fill a space larger than normally required resulting in less complexity (Panel B). Likewise, prolonging production of the upstream components increases their complexity at the expense of downstream structures (Panel C), resulting in a hypoplastic structure similar to that seen in disrupted growth of upstream components.