2025/02/07 by Yao Le, Kavitha Rajasekhar, Tricia Y. J. Loo +3 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Proteoglycans and glycosaminoglycans research #Zebrafish Biomedical Research Applications #Congenital heart defects research
paper · doi:10.1016/j.ydbio.2025.02.004
openalex publication_date 2025/02/07 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
A midline in the developing central nervous system allows symmetric distribution of neural progenitors that later establish functional, bilaterally symmetric neural circuits. In the zebrafish hindbrain, a midline forms early during neurulation as a result of coordinated cell convergence and midline-crossing cell divisions (C-divisions). These processes are controlled by the Wnt/planar cell polarity (PCP) pathway that positions progenitors close to a presumptive midline to perform C-divisions. Other upstream cues that control the extent of neural plate convergence, however, remain unclear. Midkine (Mdk) and pleiotrophin (Ptn) are structurally related heparin-binding growth factors that are dynamically expressed in the developing hindbrain. We show that two zebrafish Mdks, Mdka and Mdkb, as well as Ptn interact with distinct affinities in vivo with the protein tyrosine phosphatase receptor Ptprz1b. Zebrafish mdka and ptprz1b mutants exhibit impaired neural plate convergence along with misplaced C-divisions, defective cell polarity and transiently duplicated midlines. These defects are absent in mdka ; mdkb double mutants suggesting antagonistic roles of Mdka and Mdkb to coordinate convergence and C-divisions. Overexpression of Drosophila Prickle, a key component of the Wnt/PCP pathway, rescued the midline duplications in mdka and ptprz1b mutants that exhibited significantly reduced levels of prickle pk1b, pk2a, and pk2b expression. Ptprz1b overexpression, on the other hand, up-regulated pk2a transcription. Our findings therefore suggest roles for Mdka, Mdkb and Ptprz1b in coordinating neural plate convergence, neural progenitor positioning and midline formation by controlling the levels of prickle expression. Mdka-Ptprz1b facilitates neural plate convergence and midline formation by regulating levels of the Wnt/PCP component prickle. Illustration of convergent extension (CE), stereotypical cell-division orientation (SDO) and ectopic midline phenotypes in WT and mdka / ptprz1b mutants. In WT, Wnt/PCP signalling determines anteroposterior polarity (colored in red-blue gradient) to facilitate neural keel convergence such that C-divisions occur near the presumptive midline. After C-division, daughter cells establish apicobasal polarity (colored in magenta-cyan gradient) in a mirror symmetric manner, and opposing apical cortices form a structural midline. In contrast, in mdka and ptprz1b mutants, neural keel convergence is delayed due to impaired expression of the Wnt/PCP component prickle , causing a broadened neural keel and ectopic, disorientated C-divisions. Daughter cells establish apicobasal polarity at aberrant positions, generating duplicated midlines. • Heparin-binding growth factors Mdka, Mdkb and Ptn interact with Ptprz1receptors in vivo with distinct affinities. • Mdka and Ptprz1b but not Mdkb facilitate midline formation in the zebrafish hindbrain. • Mdka and Ptprz1b control convergence and correct positioning of polarized C-divisions. • Mdka and Ptprz1b control expression of Wnt/PCP components prickle1 , prickle2a and prickle2b.