Abstract
H6 family homeobox 1 (HMX1) regulates multiple aspects of craniofacial development as it is widely expressed in the eye, peripheral ganglia and branchial arches. Mutations in HMX1 are linked to an ocular defect termed Oculo-auricular syndrome of Schorderet-Munier-Franceschetti (MIM #612109). We identified UHRF1 as a target of HMX1 during development. UHRF1 and its partner proteins actively regulate chromatin modifications and cellular proliferation. Luciferase assays and in situ hybridization analyses showed that HMX1 exerts a transcriptional inhibitory effect on UHRF1 and a modification of its expression pattern. Overexpression of hmx1 in hsp70-hmx1 zebrafish increased uhrf1 expression in the cranial region, while mutations in the hmx1 dimerization domains reduced uhrf1 expression. Moreover, the expression level of uhrf1 and its partner dnmt1 was increased in the eye field in response to hmx1 overexpression. These results indicate that hmx1 regulates uhrf1 expression and, potentially through regulating the expression of factors involved in DNA methylation, contribute to the development of the craniofacial region of zebrafish.
Highlights
Common to vertebrates, during early embryonic development, the neural crest cells, a transient migratory cell type, migrate from the dorsal neural tube to different regions of the body and contribute to the shaping of the developing embryo [1]
A 1000-bp DNA amplicon around the transcription start site (TSS) of UHRF1 carrying all the homeobox 1 (HMX1)-binding sites identified was subcloned into the luciferase reporter pGL3-basic vector (Promega, Dubendorf, Switzerland) to produce the pGL3-Uhrf1 reporter construct for transfection in mammalian cells
We identified zinc-finger nuclease (ZFN) target sites that were exclusively comprised within exon 2 of Hmx1 (NM_001113526.1)
Summary
Common to vertebrates, during early embryonic development, the neural crest cells, a transient migratory cell type, migrate from the dorsal neural tube to different regions of the body and contribute to the shaping of the developing embryo [1]. Cranial neural crest cells (NCC) from the developing forebrain and midbrain in respect to the eye development, give rise to the corneal endothelium, sclera, iris and ciliary body stroma [2], while hindbrain derived NCC play an important role in forming the branchial arches derivatives [3]. The pharyngeal arches develop into several structures of the face and neck, including the maxillary and mandibular processes.
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