Fig. 6.

Model for HCN4 function in establishing laterality. The developmental timeline along the left illustrates early cleavage stages to post-gastrulation asymmetric gene expression of the Nodal-Lefty-Pitx2 cascade leading to final organ situs. Previously established important laterality events are outlined adjacent to the developmental time line and portray very early laterality events of cytoskeletal rearrangement and physiological amplification, as well as later events such as gastrulation-stage ciliary flows, all funnel into the canonical Nodal-Lefty-Pitx2 gene regulatory network to bring about invariant asymmetric organ situs. HCN4 action is required during early cleavage stages and can largely bypass the Nodal-Lefty asymmetric gene expression cascade to affect organ situs. HCN4-mediated Nodal-Lefty asymmetric gene expression-independent effect could be due to directly acting on downstream factors of the Nodal-Lefty pathway or through a non-canonical pathway. Players in this HCN4-mediated laterality patterning remain to be discovered.