Ontogenesis of the tear drainage system requires Prickle 1-driven polarized basement membrane (BM) deposition

Abstract

In terrestrial animals, the lacrimal drainage apparatus evolved to serve as conduits for tear flow; however, little is known about the ontogenesis of this system. Here, we defined the anatomy of the fully formed tear duct (TD) in mice, characterized crucial morphogenetic events for the development of tear duct components, and identified the site for primordial tear duct (PTD) initiation. We report that the PTD originates from the orbital lacrimal lamina (LL), a junction formed by the epithelia of the maxillary (mxp) and lateral nasal processes (lnp). We demonstrate that Prickle 1, a key component of planar cell polarity (PCP) signaling, is expressed in progenitors of the PTD and throughout tear duct morphogenesis. Disruption of Prickle 1 stalls tear duct elongation; in particular, the loss of basement membrane (BM) deposition and aberrant cytoplasmic accumulation of laminin are salient. Altered cell adhesion, cytoskeletal and vesicular transport systems, and cell axis orientation in Prickle 1 mutants support the role of Prickle 1 in PCP. Taken together, we highlight a crucial role of Prickle 1-mediated polarized BM secretion and deposition in PTD elongation.

Prickle1‐driven basement membrane deposition of the iPSC‐derived embryoid bodies is separable from the establishment of apicobasal polarity

“…24 The seemingly paradox observations could be explained when considering that AB polarity and BM basal deposition form a positive feedback loop only after their establishment (Figure 7K secretion in multiple tissues. 21,23,24 Recently, we also found that Prickle1 expression in the VE is much stronger than the epiblast in early embryogenesis. Thus, a careful in vivo characterization of the BM defect using Prickle1 conditional knockout mice combined with VE or epiblast specific Cre lines will be needed in the future to clarify which germ layer dominates BM secretion.…”

“…Loss of Prickle1 altered cytoskeleton and vesicle compartments of the epiblast and the embryonic tear-duct epithelial cells. 23,24 Interestingly, it is the disruption of microtubules or vesicle trafficking but not actin assembly that completely abolished BM. In an effort to search for proteins responsi- Although the initial BM formation is largely independent of AB polarity, as revealed by this study, studies from other systems suggest that basal BM is required for the AB polarity, [9][10][11][12] and AB polarity is also crucial for BM basal deposition.…”

“…The observed defective VE was characterized by the flattened outer surface on the Prickle1 b/b EBs (Figure 2H-J, N-P), a polarity event probably related to vectorial BM deposition during tear duct development. 23,29 To further investigate whether BM was also altered in the 3Y). The expression of Laminin receptor genes Itgb4 and a6 are also similar (Figure 3Y).…”

Obstruction of the Tear Drainage Altered Lacrimal Gland Structure and Function

“… 41 Anatomically, the nasolacrimal duct, conjunctiva, and LG epithelia are continuous and share the same origin from the embryonic conjunctival ectoderm. 25 , 42 Functionally, the lymphoid tissues of the three parts of the tear apparatus are also connected, 43 and, as a result, the nasolacrimal system plays an important role in ocular surface innate immune defense. 44 Despite the intimate relationships of the three major components of the tear apparatus, the functional connection between either of the two has not been established.…”

“… 23 , 24 Recently, we described the mouse TD ontogenesis and anatomy, demonstrating its similarity to humans using a Prickle1 mutant mouse line. 25 This is, to our knowledge, the first genetic model having incompletely developed TD (GTDOB) by disruption of Prickle1 gene. 26 – 28 …”