Disruption of Fuz in mouse embryos generates hypoplastic hindbrain development and reduced cranial nerve ganglia.

The formation of the brain and spinal cord is initiated in the earliest stages of mammalian pregnancy in a highly organized process known as neurulation. Convergent and extension movements transforms a flat sheet of ectodermal cells into a narrow and elongated line of neuroepithelia, while a major source of Sonic Hedgehog signaling from the notochord induces the overlying neuroepithelial cells to form two apposed neural folds. Afterward, neural tube closure occurs by synchronized coordination of the surface ectoderm and adjacent neuroepithelial walls at specific axial regions known as neuropores. Environmental or genetic interferences can impair neurulation resulting in neural tube defects. The Fuz gene encodes a subunit of the CPLANE complex, which is a macromolecular planar polarity effector required for ciliogenesis. Ablation of Fuz in mouse embryos results in exencephaly and spina bifida, including dysmorphic craniofacial structures due to defective cilia formation and impaired Sonic Hedgehog signaling. In this work, we demonstrate that knocking Fuz out during embryonic mouse development results in a hypoplastic hindbrain phenotype, displaying abnormal rhombomeres with reduced length and width. This phenotype is associated with persistent loss of ventral neuroepithelial stiffness, in a notochord adjacent area at the level of the rhombomere 5, preceding the development of exencephaly in Fuz ablated mutants. The formation of cranial and paravertebral ganglia is also impaired in these embryos, indicating that Fuz has a critical function sustaining normal neural tube development and neuronal differentiation. SIGNIFICANCE STATEMENT:Neural tube defects (NTDs) are a common cause of disability in children, representing the second most common congenital structural malformation in humans following only congenital cardiovascular malformations. NTDs affect approximately 1 to 2 pregnancies per 1000 births every year worldwide, when the mechanical forces folding the neural plate fails to close at specific neuropores located anteriorly (cranial) or posteriorly (caudal) along the neural tube, in a process known as neurulation, which happens throughout the third and fourth weeks of human pregnancy.