The evolution of the eye likely began with simple light-sensitive cells that allowed chordates to detect changes in light (Fritzsch and Martin, 2022, Lamb, 2013). These eyes eventually evolved into eye muscles of vertebrates that innervates unique motor neurons. This review provides an overview of eye muscles, their innervation by three motor neurons, their genetics, disorders, and vestibular input.

The extraocular muscles (EOMs) control eye movements that are innervated by three pairs of cranial nerves: the ocular motor neurons (CNIII), trochlear motor neurons (CNIV), and abducens motor neurons (CNVI). These neurons arise from their respective motor nuclei in the midbrain-brainstem and travel through the skull to innervate specific somites, the EOMs. In tetrapods, the ocular motor neurons (CNIII) control the superior rectus, inferior rectus, medial rectus, and inferior oblique muscles (Table 1). The trochlear motor neurons (CNIV) innervate the superior oblique muscle, and the abducens motor neurons (CNVI) innervates the lateral rectus muscle (LR) and has retractor bulbi (RB) in tetrapods. The coordinated action of these EOMs allows precise eye movements such as tracking a moving object or maintaining stable gaze during head movements, provided by the vestibulo-ocular reflex [VOR; (Beraneck et al., 2023, Elliott and Straka, 2022, Horn and Straka, 2021, Straka et al., 2014, Straka et al., 2022)]. In tetrapods, ocular motor neurons are derived from special somatic motor neurons (Fritzsch et al., 2017, ten Donkelaar et al., 2023) project their axons through cranial nerve III (CNIII) to form an inferior division that innervates the ipsilateral inferior rectus (IR), medial rectus (MR), and inferior oblique (IO), and a superior division that innervates the contralateral superior rectus (SR). Trochlear motor neurons are from special somatic motor neurons which project their axons through cranial nerve IV (CNIV) to innervate the contralateral superior oblique muscle (SO; Table 1). Abducens motor neurons come from somatic motor neurons which innervates cranial nerve VI (CNVI) to reach the lateral rectus muscle (LR). Epithelial mesodermal coeloms are believed to represent serial homolog of somites to generate three extraocular muscles, the EOMs which are detailed in gnathostomes and lampreys (Noden and Francis‐West, 2006, Ziermann, 2019).

The extraocular muscles are innervated by the same three cranial nerves and are typically considered identical across vertebrates (Gilland and Baker, 2005, Guthrie, 2007). That said, oculomotor, trochlear and abducens targets can vary across species. Lampreys have only three CNIII cranial branches to the extraocular muscles while gnathostomes have four CNIII cranial nerves (Table 1). The targets of cranial nerve III include the SR and nasal rectus (NR) that is innervated by a dorsal ramus including only contralateral fibers in chondrichthyans and lungfish. In contrast, the medial rectus (MR) is innervated by a ventral ramus which originates from ipsilateral fibers in bony fish, Latimeria and tetrapods (Bjerring, 1978, Fritzsch et al., 1990, Graf and Brunken, 1984, Greaney et al., 2017, Haller von Hallerstein, 1934, Nishi, 1938, Pinkus, 1895, Puzdrowski, 1998, von Bartheld, 1992). Moreover, unique to mammals, is the levator palpebrae (LP; CNIII) muscle that elevates the eyelid (Cheng et al., 2014, Newell, 1953). Trochlear motor neurons (CNIV) send their axons to exit the brainstem dorsally and then cross the midline to innervate the contralateral SO (Fritzsch et al., 1990, Haller von Hallerstein, 1934, Nieuwenhuys, 2021, Nishi, 1938). The abducens nucleus (CNVI) innervates two extraocular muscles in lampreys (the caudal and ventral rectus) but is restricted to a single EOM muscle, the lateral rectus (LR), in gnathostomes (Table 1). Basicranial muscles are likely present in all sarcopterygians (lobe-finned fishes); these muscles evolved to form the retractor bulbi in most tetrapods (Bemis and Northcutt, 1991, Bjerring, 1985, Evinger et al., 1987, Fritzsch et al., 2023, Meshida et al., 2022, Millot and Anthony, 1965, O'Reilly et al., 1996, Smith-Paredes and Bhullar, 2019, Wake, 1985). The retractor bulbi (Table 1) are reduced or absent in derived microchiroptera and primates (Machado et al., 2007, Schnyder, 1984). Overall, the three ocular cranial nerves and associated extraocular muscles develop in a stereotyped fashion that is best understood from research in mice, chicken, frogs, zebrafish and lampreys (Chagnaud et al., 2017, Elliott and Straka, 2022, Greaney et al., 2017, Michalak et al., 2017, Noden and Francis‐West, 2006).

Eye muscle innervation, their growth, guidance and perturbation of extraocular muscles: The growth and guidance of axons is a complex process that involves the coordinated action of many genes, and any disruptions or mutations in these genes can lead to abnormal development of the nervous system and related disorders. Several developmental defects (Kif21A, CHN1, CXCR4, ACKR3) are associated with the Sema3 gene family, involving genes that interact with neuropilins (Npn1/2) and Plexina1/2 to control trochlear decussation (Chilton and Guthrie, 2017, Whitman, 2021). Netrin-1 repels the trochlear axons that cooperates with Unc5 (Burgess et al., 2006, Colamarino and Tessier-Lavigne, 1995, Jahan et al., 2021). The loss of genes Slit1/2 and Robo1/2 can likewise result in aberrant connections of trochlear axons (Bjorke et al., 2016, Bjorke et al., 2021, Kim et al., 2019). Defects in axon guidance are associated with genes Robo3, Col25a1, cadherins and there are also various Tubb gene-related defects and gain-of function mutations (Bjorke et al., 2021, Knüfer et al., 2020, Tischfield and Engle, 2010, Whitman, 2021).

Among these genes are those controlling the projections that can be the source of developmental defects. In mice, certain mutations result in the reduction or gain-of-function of these two muscles, SR and LP, resulting in ptosis due to the inability to lift the eyes and lids (Cheng, et al., 2014). Perturbations in the growth and guidance of ocular cranial nerves can cause paralytic strabismus, which is one of a number of congenital cranial dysinnervation disorders (CCDDs;(Engle, 2010;Guthrie, 2007)). In addition, axons can make targeting errors implicating aberrant cell body migration and axon extension, including Duan retraction syndrome and Möbius syndrome (ten Donkelaar et al., 2023, Whitman, 2021).

Vestibular inputs to the motor neurons: The eye muscle motor neurons are themselves innervated by vestibular nuclei (Straka and Baker, 2013, Straka et al., 2014, Straka et al., 2022). Vestibular inputs to eye muscle motor neurons display different patterns of connections in lampreys, chondrichthyans, and Osteichthyes (Evinger et al., 1987, Fritzsch, 1998, Glover, 2020, Graf and Brunken, 1984). Among teleosts, frogs, birds, and mammals have a specific pattern of innervation by vestibular inputs to reach out the midbrain-hindbrain connections (Chagnaud et al., 2017, Greaney et al., 2017, Horn and Straka, 2021, Straka and Baker, 2013, Straka et al., 2014). By contrast, studies in chondrichthyans (cartilaginous fishes) revealed a different pattern with a combination of ipsilateral and contralateral nerve fibers (Graf and Brunken, 1984, Puzdrowski, 1998). Many details of vestibular relationships are incomplete in lampreys (which lack a horizontal canal) but can be compared to the pattern of connections in gnathostomes (Fritzsch, 1998, Fritzsch et al., 2023, Fritzsch et al., 2001, Straka and Baker, 2013, Wibble et al., 2022).

Connection of three eye muscles motor neurons that innervate distinct EOMs will be described in 2 Extraocular muscles, 3 Extraocular muscles form from three distinct sources. Next, the genetic basis of how and why different ocular motor neuron innervate the ocular muscles in vertebrates will be provided (4 Development and axon guidance, 5 Molecular properties of ocular motor neurons (III, IV and VI)) with an overview of axonal defects in mutant mice and humans, detailing the congenital cranial dysinnervation disorders (Section 6). Vestibular nuclei connections differ between the eyes and ears across vertebrates (Section 7).