Neutral sphingomyelinase (SMPD3) deficiency disrupts the Golgi secretory pathway and causes growth inhibition

Abstract

Systemic loss of neutral sphingomyelinase (SMPD3) in mice leads to a novel form of systemic, juvenile hypoplasia (dwarfism). SMPD3 deficiency in mainly two growth regulating cell types contributes to the phenotype, in chondrocytes of skeletal growth zones to skeletal malformation and chondrodysplasia, and in hypothalamic neurosecretory neurons to systemic hypothalamus–pituitary–somatotropic hypoplasia. The unbiased smpd3−/− mouse mutant and derived smpd3−/− primary chondrocytes were instrumental in defining the enigmatic role underlying the systemic and cell autonomous role of SMPD3 in the Golgi compartment. Here we describe the unprecedented role of SMPD3. SMPD3 deficiency disrupts homeostasis of sphingomyelin (SM), ceramide (Cer) and diacylglycerol (DAG) in the Golgi SMPD3-SMS1 (SM-synthase1) cycle. Cer and DAG, two fusogenic intermediates, modify the membrane lipid bilayer for the initiation of vesicle formation and transport. Dysproteostasis, unfolded protein response, endoplasmic reticulum stress and apoptosis perturb the Golgi secretory pathway in the smpd3−/− mouse. Secretion of extracellular matrix proteins is arrested in chondrocytes and causes skeletal malformation and chondrodysplasia. Similarly, retarded secretion of proteo-hormones in hypothalamic neurosecretory neurons leads to hypothalamus induced combined pituitary hormone deficiency. SMPD3 in the regulation of the protein vesicular secretory pathway may become a diagnostic target in the etiology of unknown forms of juvenile growth and developmental inhibition.

Photodynamic therapy with redaporfin targets the endoplasmic reticulum and Golgi apparatus

“…Similarly, specific removal of GA‐relevant proteins can precipitate neurodegeneration in mice (Liu et al , ) . Systemic loss of neutral sphingomyelinase (SMPD3) can cause dwarfism with chondrodysplasia due to GA dysfunction that may be secondary to the altered metabolism of ceramide and diacylglycerol (Stoffel et al , ). Hypoxia reportedly compromises the survival and function of pancreatic β‐cells by ER‐to‐GA protein trafficking coupled to the depletion of proteins from the coatomer protein complex (COP1; Bensellam et al , ).…”

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis

“…Inactivation of Smpd3, the murine homolog of human SMPD3, impairs Golgi vesicular transport, perturbs protein homeostasis, and induces ER stress, leading to apoptosis, growth inhibition, and development retardation in mice. 9 To date, human variants have only been reported in SMPD1, causing lysosomal storage disorders Niemann-Pick disease type A and B (MIM: 607608).…”

Neutral Sphingomyelinase 2 (SMPD3) Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization

“…SMPD3 is restricted to the perturbation of the Golgi secretory pathway in chondrocytes, ECM protein secretion, transport, and extracellular apposition in the epiphyseal growth zone for longitudinal growth. 13 Here, we show that SMPD3 deficiency leaves mineralization, the essential step during bone ossification, unaffected.…”

“…Primary chondrocytes in culture were instrumental in unveiling the mechanism underlying the absence of SMPD3 in the sphingomyelin cycle of the Golgi compartment: Golgi membrane budding, the initial step for multiform vesicle formation, transport, and secretion in the Golgi secretory pathway is impaired and leads to dysproteostasis and intracellular accumulation of extracellular matrix proteins (ECM) in the ERtubular system and Golgi complex. 13 Perturbation of the Golgi secretory pathway in chondrocytes of the epiphyseal growth plate leads to inhibition of longitudinal growth, malformation of long bones, and chondrodysplasia. 10 SMPD3 deficiency in hypothalamic neurosecretory neurons during the postnatal growth phase impedes the hypothalamusepituitary growth axis and causes combined pituitary hormone deficiencyeassociated systemic hypoplasia.…”

“…10 SMPD3 deficiency in hypothalamic neurosecretory neurons during the postnatal growth phase impedes the hypothalamusepituitary growth axis and causes combined pituitary hormone deficiencyeassociated systemic hypoplasia. 13 The comprehensive studies of the phenotype of the Smpd3 -/mouse, 3,9,11 generated by targeted ablation of the Smpd3 locus, critically differs from the phenotype of the fragilitas ossium (fro/fro) mouse mutant, a mutant mouse strain, which has been isolated from stock of mice that were chemically mutagenized randomly. 14,15 The phenotype of the fro/fro mutant is characterized by a chromosomal deletion, which includes the smpd3 locus.…”