Rax regulates hypothalamic tanycyte differentiation and barrier function in mice.
The wall of the ventral third ventricle is composed of two distinct cell populations: tanycytes and ependymal cells. Tanycytes regulate many aspects of hypothalamic physiology, but little is known about the transcriptional network that regulates their development and function. We observed that the retina and anterior neural fold homeobox transcription factor (Rax) is selectively expressed in hypothalamic tanycytes, and showed a complementary pattern of expression to markers of hypothalamic ependymal cells, such as Rarres2 (retinoic acid receptor responder [tazarotene induced] 2). To determine whether Rax controls tanycyte differentiation and function, we generated Rax haploinsufficient mice and examined their cellular and molecular phenotype in adulthood. These mice appeared grossly normal, but careful examination revealed a thinning of the third ventricular wall and reduction of both tanycyte and ependymal markers. These experiments show that Rax is required for hypothalamic tanycyte and ependymal cell differentiation. Rax haploinsufficiency also resulted in the ectopic presence of ependymal cells in the α2 tanycytic zone, where few ependymal cells are normally found, suggesting that Rax is selectively required for α2 tanycyte differentiation. These changes in the ventricular wall were associated with reduced diffusion of Evans Blue tracer from the ventricle to the hypothalamic parenchyma, with no apparent repercussion on the gross anatomical or behavioral phenotype of these mice. In conclusion, we have provided evidence that Rax is required for the normal differentiation and patterning of hypothalamic tanycytes and ependymal cells, as well as for maintenance of the cerebrospinal fluid-hypothalamus barrier.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287; Institute of Medical Research, Universidad de Antioquia, School of Medicine, Medellín, Colombia 05001000.
Ana L
AL
Miranda-Angulo
Mardi S
MS
Byerly
Janny
J
Mesa
Hong
H
Wang
Seth
S
Blackshaw
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D018925:Chemokines; D002630:Chemotactic Factors / Q000378:metabolism; D063928:Ependymoglial Cells / Q000502:physiology*; D005070:Evans Blue; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007031:Hypothalamus / Q000166:cytology* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020542:Third Ventricle / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D018925:Chemokines; D002630:Chemotactic Factors; D005136:Eye Proteins; C509755:Gpr50 receptor, mouse; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C105441:Rax protein, mouse; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C523686:chemerin protein, mouse; D005070:Evans Blue
CSF-Brain barrier; Rarres2 expression; Rax haploinsufficiency; ectopic ependymal cells; thinning of the third ventricular wall