Caroline Valdes

Background:  Cyclopia is a rare and devastating craniofacial malformation characterized by the failure of midline facial and forebrain structures to separate. It is the most severe manifestation of holoprosencephaly and results in a single eye and fused brain hemispheres. Although it has long been associated with disruptions in early embryonic patterning, recent research has identified the Sonic Hedgehog (SHH) signaling pathway as a key regulator of embryonic midline patterning, particularly in the development of the forebrain and facial structures^1-3. Disruptions in SHH signaling, including cilia-dependent signal transduction and interactions with neural crest cells (NCCs), have been strongly implicated in the pathogenesis of cyclopia^2-4. Understanding these mechanisms is essential for identifying potential therapeutic strategies in craniofacial malformations that currently lack treatment options.

Objective:  To review and synthesize recent findings from animal and human studies investigating how disruptions in the SHH signaling pathway, particularly involving primary cilia and NCCs, lead to midline craniofacial malformations, with a focus on cyclopia.

Search Methods:  A literature search was conducted using PubMed to identify relevant peer-reviewed studies published in the last 7 years. Search terms included “Sonic hedgehog,” “cyclopia,” “primary cilia,” “neural crest cells,” “craniofacial development,” and “holoprosencephaly.” Five primary studies using chick, mouse, and zebrafish models were selected for in-depth analysis.

Results:  SHH knockout models showed midline fusion defects, optic vesicle failure, and cyclopia^1-5. Primary cilia were found essential for SHH signal transduction, particularly in NCCs, which rely on SHH to regulate polarity, migration, and directional cell division³. Mouse models with conditional cilia deletion in NCCs exhibited disrupted SHH feedback to the forebrain, contributing to midline widening and cyclopia-like phenotypes³. Zebrafish mutants with impaired ciliary function also showed defective frontonasal development and ocular anomalies^4,5. Additionally, SHH was shown to sense mechanical stress during morphogenesis, and its absence disrupted organized tissue growth¹. Emerging research has identified potential interventions, such as gene therapy to restore ciliary function or modulate SHH pathway components like SET/I2PP2A⁵.

Conclusions:  SHH signaling plays a central role in orchestrating the coordinated development of the forebrain and midline facial structures, with its disruption resulting in severe craniofacial anomalies such as cyclopia¹. The pathway operates through cilia-dependent mechanisms in NCCs that are vital for maintaining cellular polarity and tissue architecture³. These findings have substantial implications for both our understanding of craniofacial morphogenesis and the development of targeted interventions. Therapeutically, strategies aimed at restoring primary cilia function or modulating SHH responsiveness, such as gene therapies targeting ciliary proteins or regulators like PTCH1 and SET/I2PP2A, may offer future avenues for correcting or preventing midline defects^3,5. Furthermore, identifying critical developmental windows for SHH supplementation and establishing genetic screening protocols could enhance early diagnosis and prenatal intervention for at-risk populations^1,2. A better understanding of the interplay between SHH, cilia function, and neural crest biology may ultimately lead to novel therapies for a wide range of congenital craniofacial disorders.

Work Cited:

1. Ohtsuka D, Kida N, Lee SW, Kawahira N, Morishita Y. Cell disorientation by loss of SHH-dependent mechanosensation causes cyclopia. Sci Adv. Jul 15 2022;8(28):eabn2330. doi:10.1126/sciadv.abn2330
2. Abrams SR, Reiter JF. Ciliary Hedgehog signaling regulates cell survival to build the facial midline. Elife. Oct 21 2021;10doi:10.7554/eLife.68558
3. Schock EN, Brugmann SA. Neural crest cells utilize primary cilia to regulate ventral forebrain morphogenesis via Hedgehog-dependent regulation of oriented cell division. Dev Biol. Nov 15 2017;431(2):168-178. doi:10.1016/j.ydbio.2017.09.026
4. Nandamuri SP, Lusk S, Kwan KM. Loss of zebrafish dzip1 results in inappropriate recruitment of periocular mesenchyme to the optic fissure and ocular coloboma. PLoS One. 2022;17(3):e0265327. doi:10.1371/journal.pone.0265327
5. Serifi I, Besta S, Karetsou Z, et al. Targeting of SET/I2PP2A oncoprotein inhibits Gli1 transcription revealing a new modulator of Hedgehog signaling. Sci Rep. Jul 6 2021;11(1):13940. doi:10.1038/s41598-021-93440-0