Neuronal Developmental Marker FORSE-1 Identifies a Putative Progenitor of the Pulmonary Neuroendocrine Cell Lineage During Lung Development

Abstract

S U M M A R YThe FORSE-1 ( fore brain-s urface-e mbryonic) monoclonal antibody (MAb) recognizes a carbohydrate cell surface epitope related to the Lewis-X (LeX) and stage-specific embryonic antigens (SSEAs). In the developing CNS, the FORSE-1 epitope is believed to serve as a marker of progenitor cells. We studied the expression of the FORSE-1 epitope in pulmonary neuroendocrine cells (PNECs) and related neuroepithelial bodies (NEBs), cell types implicated in paracrine regulation of lung development. We used dual immunolabeling to identify PNECs/NEBs in tissue sections from developing rabbit fetal lungs and corresponding primary lung cell cultures. During the early stage (E16), the FORSE-1 MAb labeled primitive airway epithelium, whereas serotonin (5HT) immunoreactivity, a marker of PNEC/ NEB differentiation, was negative. After E18, FORSE-1 labeling became restricted to PNECs and NEBs, identified by co-expression with 5HT, then decreased coincident with an increase in 5HT. Expression of the FORSE-1 epitope correlated inversely with 5HT expression in PNEC/NEB cells. FORSE-1 immunoreactivity correlated with cell proliferation assessed by BrdU labeling. Downregulation of the FORSE-1 epitope correlated with maturation of PNECs/NEBs. The presence of few FORSE-1/5HT-positive cells in postnatal lung suggests retention of progenitors. The FORSE-1 epitope was associated with a high molecular weight (286 kD) glycoprotein that decreased with increasing gestational age, as demonstrated by immunoblotting. Overall expression of SSEA-1, -3, and -4 antigens was similar to FORSE-1/ 5HT, although the former was preferentially localized to neurite-like processes. Because the role of the FORSE-1 epitope in the CNS probably involves cell adhesion and differentiation, we propose a similar function in developing lung. The demonstration of LeX/SSEA antigen expression in the PNEC/NEB cell lineage underscores the importance of these cells in developing lung. Furthermore, the FORSE-1 antigen may identify committed progenitors of the PNEC/NEB cell system.

Eyes absent 1 (Eya1) is a critical coordinator of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung

“…1J-L). Thus, Eya1 protein continues to be expressed postnatally in cells with putative lung epithelial progenitor potential: neuroendocrine bodies (NEB; Pan et al, 2000; Reynolds et al, 2000; Hong el al., 2001; Giangreco et al, 2004; Fig. 1J-L).…”

Pulmonary Neuroendocrine Cell System in Pediatric Lung Disease—Recent Advances

“…To identify the putative progenitors of PNEC we have used an antibody against an early neuronal developmental marker, FORSE-1, that recognizes the forebrain-surface-embryonic antigen expressed on progenitor cells in the developing central nervous system (CNS) [28]. In early rabbit fetal lungs (E16), FORSE-1 antibody labeled all cells of the primitive airway epithelium and later became restricted to 5-HT immunopositive PNEC/NEB.…”

Functional facets of the pulmonary neuroendocrine system

“…It is currently thought that PNECs like their counterparts in the gastrointestinal tract are derived from multipotent epithelial progenitors as alluded before, and that all epithelial cells arise from a single stem cell. 47,48 In order to define the putative progenitors for the PNEC lineage during lung development Pan et al 49 recently turned to the neuronal developmental marker FORSE-1, the forebrain-surface-embryonic monoclonal antibody. The FORSE-1 epitope serves as a marker of progenitor cells in the earliest forebrain region of the mammalian central nervous system.…”