A computational model reveals the remarkable patterning potential of the Wnt–FGF gene regulatory network in the posterior lateral line primordium

Abstract

Loss and gain of Hedgehog (Hh) function in humans cause craniofacial and brain abnormalities such as holoprosencephaly and Gorlin and Grieg syndromes respectively. Holoprosencephaly is associated primarily with mutations in SHH, while Gorlin and Grieg syndromes have been mapped to mutations in PATCHED1 and GLI3. Hh signaling therefore is critically required for proper craniofacial and brain development and must be tightly regulated, however our understanding of the gene and protein networks governing Hh signaling remains incomplete. To identify new Hh protein signaling complexes (“Hedgehogome”) we performed proteomic analyses of mammalian Hh signaling proteins using (1) flag tagged Hh proteins expressed in human Hek293 and stable mouse NIH3T3 cell line and (2) cell-free protein synthesis together with mouse embryo lysates. These approaches have successfully identified novel candidate proteins that are important for mediating Hh signaling. Here we describe the function of A kinase anchoring protein (AKAP11) which associates with the Hh receptor, Patched1 and Hh transducer, smoothened to modulate cell death, proliferation and dorso-ventral patterning of neural tube via PKA signaling activity.