Kinesin superfamily proteins (KIFs) are evolutionary conserved microtubule-associated proteins involved in diverse cellular processes, including intracellular transport, microtubule dynamics, cell division, and signaling transduction [[1], [2], [3]]. Accumulating studies suggest that kinesin mutations are related to a variety of human diseases with recurrent phenotypical themes, including microcephaly, brain malformations, retinopathy, and birth defects [[4], [5], [6]]. Kinesin motors act in concert with microtubule and microtubule-associated proteins to promote cell proliferation of neuronal progenitors, migration of neurons, and intracellular trafficking in developing neurons and dendrites [7,8]. Kinesin-5 KIF11 (also known as Eg5) is a bipolar homotetrameric motor that slides antiparallel microtubules apart, separates spindle poles, and maintains spindle architecture during cell division [[9], [10], [11], [12]]. In humans, patients carrying KIF11 mutations result in microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development (MCLMR; OMIM 152950), which is a complex autosomal dominant disease characterized by microcephaly, ocular development anomalies, dysmorphic facial phenotypes and developmental delay [[13], [14], [15], [16], [17], [18], [19]]. However, how KIF11 deficiency causes the MCLMR syndrome in patients with KIF11 mutations remains elusive.

Chemical inhibition, RNA interference, and genetic deletion of KIF11 proteins leads to the formation of monopolar spindle, defects in centrosome separation, and metaphase arrest during mitosis [9,11,[20], [21], [22]]. In mice, genetic deletion of KIF11 results in spindle defects and cell cycle arrest, resulting in early embryonic lethality in pre-implantation embryos [23,24], which is an obstacle for the studies of developmental roles of KIF11. Furthermore, endothelial cell-conditional KIF11 knockout mice display severe retinal disorders, including defects in endothelial cell proliferation and retinal vascular development [25].

Homozygous mutations in centrosomal proteins MCPH1-7 [26,27], WDR62 [28], CDK5RAP2 [29], CEP152 [30], ASPM [31], CENPJ [29], and STIL [32] results in autosomal recessive primary microcephaly (MCPH; MIM251200). Interestingly, the majority of microcephaly-related genes encode centrosomal proteins, which play a vital role in centriole duplication, centrosome maturation, spindle assembly, microtubule dynamics, and cell cycle regulation [[32], [33], [34]]. These studies indicate centrosome duplication cycle and centrosome functions are closely related to primary microcephaly [27,33]. Kinesin-5 KIF11 is an emerging novel regulator in microcephaly and related syndromes [7,15]. Subcellular localization of KIF11 protein at centrosomes and its core functions in centrosome separation in mitosis suggest a different pathway in KIF11-related microcephaly [35,36]. The casual relationship between KIF11 mutations and MCLMR is well established, however, the underlying cellular and molecular mechanisms underlying KIF11-related MCLMR remain unclear.

In this study, we describe the detailed cellular mechanisms for loss-of-functions of KIF11 in microcephaly and retinopathy. By simultaneously investigating the chick and zebrafish models, we find that loss-of-function of KIF11 proteins is associated with the premature switch from symmetric to asymmetric cell division, mitotic defects, and apoptotic cell death, eventually contributing to the loss of neural progenitor cells, smaller brain size, and retinopathy. We provide evidence that KIF11 is essential for bipolar spindle assembly and chromosome alignment in progenitor stem cells during neurogenic cell division. Our findings have revealed that KIF11 inhibition mainly suppresses cell cycle progression, induces the formation of polyploid cells, and alters the symmetric division of progenitor cells, which could shed light on the mechanisms of reduced neuroepithelium, microcephaly, and chorioretinopathy in MCLMR patients.