Talk:Vision - Extraocular Muscle Development

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Cite this page: Hill, M.A. (2020, July 13) Embryology Vision - Extraocular Muscle Development. Retrieved from


Palisade Endings Are a Constant Feature in the Extraocular Muscles of Frontal-Eyed, But Not Lateral-Eyed, Animals

Invest Ophthalmol Vis Sci. 2016 Feb 1;57(2):320-31. doi: 10.1167/iovs.15-18716.

Blumer R1, Maurer-Gesek B1, Gesslbauer B2, Blumer M3, Pechriggl E3, Davis-López de Carrizosa MA4, Horn AK5, May PJ6, Streicher J7, de la Cruz RR4, Pastor ÁM4.


PURPOSE: To test whether palisade endings are a general feature of mammalian extraocular muscles (EOMs). METHODS: Thirteen species, some frontal-eyed (human, monkey, cat, and ferret), and others lateral-eyed (pig, sheep, calf, horse, rabbit, rat, mouse, gerbil, and guinea pig) were analyzed. Palisade endings were labeled by using different combinations of immunofluorescence techniques. Three-dimensional reconstructions of immunolabeled palisade endings were done. RESULTS: In all frontal-eyed species, palisade endings were a consistent feature in the rectus EOMs. Their total number was high and they exhibited an EOM-specific distribution. In particular, the number of palisade endings in the medial recti was significantly higher than in the other rectus muscles. In the lateral-eyed animals, palisade endings were infrequent and, when present, their total number was rather low. They were only found in ungulates (sheep, calf, pig, and horse) and in rabbit. In rodents (rat, guinea pig, mouse, and gerbil) palisade endings were found infrequently (e.g., rat) or were completely absent. Palisade endings in frontal-eyed species and in some lateral-eyed species (pig, sheep, calf, and horse) had a uniform morphology. They generally lacked α-bungarotoxin staining, with a few exceptions in primates. Palisade endings in other lateral-eyed species (rabbit and rat) exhibited a simplified morphology and bound α-bungarotoxin. CONCLUSIONS: Palisade endings are not a universal feature of mammalian EOMs. So, if they are proprioceptors, not all species require them. Because in frontal-eyed species, the medial rectus muscle has the highest number of palisade endings, they likely play a special role in convergence.

PMID 26830369


Eyelid closure in embryogenesis is required for ocular adnexa development

Invest Ophthalmol Vis Sci. 2014 Nov 6;55(11):7652-61. doi: 10.1167/iovs.14-15155.

Meng Q1, Mongan M1, Carreira V1, Kurita H1, Liu CY2, Kao WW2, Xia Y3.


PURPOSE: Mammalian eye development requires temporary fusion of the upper and lower eyelids in embryogenesis. Failure of lid closure in mice leads to an eye open at birth (EOB) phenotype. Many genetic mutant strains develop this phenotype and studies of the mutants lead to a better understanding of the signaling mechanisms of morphogenesis. The present study investigates the roles of lid closure in eye development. METHODS: Seven mutant mouse strains were generated by different gene ablation strategies that inactivated distinct signaling pathways. These mice, including systemic ablation of Map3k1 and Dkk2, ocular surface epithelium (OSE) knockout of c-Jun and Egfr, conditional knockout of Shp2 in stratified epithelium (SE), as well as the Map3k1/Jnk1 and Map3k1/Rhoa compound mutants, all exhibited defective eyelid closure. The embryonic and postnatal eyes in these mice were characterized by histology and immunohistochemistry. RESULTS: Some eye abnormalities, such as smaller lens in the Map3k1-null mice and Harderian gland hypoplasia in the Dkk2-null mice, appeared to be mutant strain-specific, whereas other abnormalities were seen in all mutants examined. The common defects included corneal erosion/ulceration, meibomian gland hypoplasia, truncation of the eyelid tarsal muscles, failure of levator palpebrae superioris (LPS) extension into the upper eyelid and misplacement of the inferior oblique (IO) muscle and inferior rectus (IR) muscle. The muscle defects were traced to the prenatal fetuses. CONCLUSIONS: In addition to providing a protective barrier for the ocular surface, eyelid closure in embryogenesis is required for the development of ocular adnexa, including eyelid and extraocular muscles. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. KEYWORDS: LPS; embryonic eyelid closure; extraocular muscles; ocular adnexa; tarsal muscles

PMID 25377219


The role of Pitx2 in maintaining the phenotype of myogenic precursor cells in the extraocular muscles

PLoS One. 2013;8(3):e58405. doi: 10.1371/journal.pone.0058405. Epub 2013 Mar 7.

Hebert SL, Daniel ML, McLoon LK. Source Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.


Many differences exist between extraocular muscles (EOM) and non-cranial skeletal muscles. One striking difference is the sparing of EOM in various muscular dystrophies compared to non-cranial skeletal muscles. EOM undergo continuous myonuclear remodeling in normal, uninjured adults, and distinct transcription factors are required for the early determination, development, and maintenance of EOM compared to limb skeletal muscle. Pitx2, a bicoid-like homeobox transcription factor, is required for the development of EOM and the maintenance of characteristic properties of the adult EOM phenotype, but is not required for the development of limb muscle. We hypothesize that these unique properties of EOM contribute to the constitutive differences between EOM and non-craniofacial skeletal muscles. Using flow cytometry, CD34(+)/Sca1(-/)CD45(-/)CD31(-) cells (EECD34 cells) were isolated from extraocular and limb skeletal muscle and in vitro, EOM EECD34 cells proliferated faster than limb muscle EECD34 cells. To further define these myogenic precursor cells from EOM and limb skeletal muscle, they were analyzed for their expression of Pitx2. Western blotting and immunohistochemical data demonstrated that EOM express higher levels of Pitx2 than limb muscle, and 80% of the EECD34 cells expressed Pitx2. siRNA knockdown of Pitx2 expression in EECD34 cells in vitro decreased proliferation rates and impaired the ability of EECD34 cells to fuse into multinucleated myotubes. High levels of Pitx2 were retained in dystrophic and aging mouse EOM and the EOM EECD34 cells compared to limb muscle. The differential expression of Pitx2 between EOM and limb skeletal muscle along with the functional changes in response to lower levels of Pitx2 expression in the myogenic precursor cells suggest a role for Pitx2 in the maintenance of constitutive differences between EOM and limb skeletal muscle that may contribute to the sparing of EOM in muscular dystrophies.

PMID 23505501

Thyroid hormone and retinoic acid interact to regulate zebrafish craniofacial neural crest development

Dev Biol. 2013 Jan 15;373(2):300-9. doi: 10.1016/j.ydbio.2012.11.005. Epub 2012 Nov 17.

Bohnsack BL, Kahana A. Source Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA.


Craniofacial and ocular morphogenesis require proper regulation of cranial neural crest migration, proliferation, survival and differentiation. Although alterations in maternal thyroid hormone (TH) are associated with congenital craniofacial anomalies, the role of TH on the neural crest has not been previously described. Using zebrafish, we demonstrate that pharmacologic and genetic alterations in TH signaling disrupt cranial neural crest migration, proliferation, and survival, leading to craniofacial, extraocular muscle, and ocular developmental abnormalities. In the rostral cranial neural crest that gives rise to the periocular mesenchyme and the frontonasal process, retinoic acid (RA) rescued migratory defects induced by decreased TH signaling. In the caudal cranial neural crest, TH and RA had reciprocal effects on anterior and posterior pharyngeal arch development. The interactions between TH and RA signaling were partially mediated by the retinoid X receptor. We conclude that TH regulates both rostral and caudal cranial neural crest. Further, coordinated interactions of TH and RA are required for proper craniofacial and ocular development. Copyright © 2012 Elsevier Inc. All rights reserved.

PMID 23165295


Development of extraocular muscles requires early signals from periocular neural crest and the developing eye

Arch Ophthalmol. 2011 Aug;129(8):1030-41. doi: 10.1001/archophthalmol.2011.75. Epub 2011 Apr 11.

Bohnsack BL, Gallina D, Thompson H, Kasprick DS, Lucarelli MJ, Dootz G, Nelson C, McGonnell IM, Kahana A. Source Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, 48105, USA.


OBJECTIVES: To identify and explain morphologic changes of the extraocular muscles (EOMs) in anophthalmic patients. METHODS: Retrospective medical record review of patients with congenital anophthalmia, using magnetic resonance imaging and intraoperative findings to characterize EOM morphology. We then used molecular biology techniques in zebrafish and chick embryos to determine the relationships among the developing eye, periocular neural crest, and EOMs. RESULTS: In 3 human patients with bilateral congenital anophthalmia and preoperative orbital imaging, we observed a spectrum of EOM morphologies ranging from indiscernible muscle tissue to well-formed, organized EOMs. Timing of eye loss in zebrafish and chick embryos correlated with the morphology of EOM organization in the orbit (eye socket). In congenitally eyeless Rx3 zebrafish mutants, or following genetic ablation of the cranial neural crest cells, EOMs failed to organize, which was independent of other craniofacial muscle development. CONCLUSIONS: Orbital development is dependent on interactions between the eye, neural crest, and developing EOMs. Timing of the ocular insult in relation to neural crest migration and EOM development is a key determinant of aberrant EOM organization. Additional research will be required to study patients with unilateral and syndromic anophthalmia and assess for possible differences in clinical outcomes of patients with varied EOM morphology. CLINICAL RELEVANCE: The presence and organization of EOMs in anophthalmic eye sockets may serve as a markers for the timing of genetic or teratogenic insults, improving genetic counseling, and assisting with surgical reconstruction and family counseling efforts. Comment in What experimental embryology can teach us about the development of the extraocular muscles in anophthalmia: at the interface of basic and clinical sciences. [Arch Ophthalmol. 2011]

PMID 21482859