Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin

• Published in: Nature communications Vol. 12; no. 1; pp. 6271 - 20
• Main Authors: Wang, Jialiang S., Kamath, Tushar, Mazur, Courtney M., Mirzamohammadi, Fatemeh, Rotter, Daniel, Hojo, Hironori, Castro, Christian D., Tokavanich, Nicha, Patel, Rushi, Govea, Nicolas, Enishi, Tetsuya, Wu, Yunshu, da Silva Martins, Janaina, Bruce, Michael, Brooks, Daniel J., Bouxsein, Mary L., Tokarz, Danielle, Lin, Charles P., Abdul, Abdul, Macosko, Evan Z., Fiscaletti, Melissa, Munns, Craig F., Ryder, Pearl, Kost-Alimova, Maria, Byrne, Patrick, Cimini, Beth, Fujiwara, Makoto, Kronenberg, Henry M., Wein, Marc N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/91; 45; 631/136/815/816; 631/136/818; 64; 64/110; 692/163/2743/316/799; Adolescent; Animals; Binding sites; Biomedical materials; Bone diseases; Bone Diseases - genetics; Bone Diseases - metabolism; Bone Diseases - physiopathology; Bone matrix; Circuits; Defects; Dendrites; Dendrites - metabolism; Female; Gene deletion; Gene Expression Regulation; Gene sequencing; Genes; Humanities and Social Sciences; Humans; Male; Maturation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morphology; multidisciplinary; Muscle Proteins - genetics; Muscle Proteins - metabolism; Mutation; Neural networks; Osteoblasts; Osteocytes; Osteocytes - metabolism; Science; Science (multidisciplinary); Sp7 Transcription Factor - genetics; Sp7 Transcription Factor - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26571-7

Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during “osteocytogenesis” is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites. Profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates defects in osteocyte maturation in the absence of Sp7. Sp7-dependent osteocyte gene networks are associated with human skeletal diseases. Moreover, humans with a SP7 R316C mutation show defective osteocyte morphology. Sp7-dependent genes that mark osteocytes are enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. These findings reveal a role for Sp7 and its target gene Osteocrin in osteocytogenesis, revealing that pathways that control osteocyte development influence human bone diseases. The molecular circuitry that drives dendrite formation during osteocytogenesis remains poorly understood. Here the authors show that deletion of Sp7, a gene linked to rare and common skeletal disease, in mature osteoblasts and osteocytes causes severe defects in osteocyte dendrites.