SHH and spina bifida: In contrast, elevated activity of the Shh signaling pathway downstream of Shh due to the loss of negative regulators such as Ptch1, Rab23, Tulp3 or Sufu [13] leads to elevated signaling in the dorsal neural folds, inhibiting development of the DLHP (e.g., Tulp3 [35]) and causing NTD (exencephaly and sometimes caudal spina bifida) in the regions that normally have DLHP (Figure 2).